Pharmaceutical compositions of dispersions of amorphous drugs mixed with polymers

ABSTRACT

A pharmaceutical composition comprises a dispersion comprising a low-solubility drug and a matrix combined with a concentration-enhancing polymer. At least a major portion of the drug is amorphous in the dispersion. The compositions improve the stability of the drug in the dispersion, and/or the concentration of drug in a use environment.

[0001] This application claims the benefit of priority of provisionalPatent Application Serial No. 60/300,261 filed Jun. 22, 2001, which isincorporated herein by reference in its entirety for all purposes.

BACKGROUND OF THE INVENTION

[0002] The invention relates to compositions of a dispersion comprisingamorphous drug and a matrix combined with a concentration-enhancingpolymer that improves the stability of the drug and/or enhances theconcentration of the drug in a use environment.

[0003] Low-solubility drugs often show poor bioavailability or irregularabsorption, the degree of irregularity being affected by factors such asdose level, fed state of the patient, and form of the drug. Increasingthe bioavailability of low-solubility drugs has been the subject of muchresearch. Increasing bioavailability hinges on improving theconcentration of the drug in solution to improve absorption.

[0004] It is well known that the amorphous form of a low-solubility drugthat is capable of existing in either the crystalline or amorphous formmay temporarily provide a greater aqueous concentration of drug relativeto the equilibrium concentration obtained by dissolution of drug in ause environment. Such amorphous forms may consist of the amorphous drugalone, a dispersion of the drug in a matrix material, or the drugadsorbed onto a substrate. It is believed that such amorphous forms ofthe drug may dissolve more rapidly than the crystalline form, oftendissolving faster than the drug can precipitate from solution. As aresult, the amorphous form may temporarily provide a greater-thanequilibrium concentration of drug.

[0005] While such amorphous forms may show initially enhancedconcentration of the drug in a use environment, nevertheless theimproved concentration is often short-lived. Typically, the initiallyenhanced drug concentration is only temporary and quickly returns to thelower equilibrium concentration.

[0006] One approach to increase the bioavailability of low-solubilitydrugs has involved forming amorphous dispersions of drugs with polymers.Examples of attempts to increase drug concentration by forming adispersion of the drug with a polymer include Lahr et al., U.S. Pat. No.5,368,864, Kanikanti et al., U.S. Pat. No. 5,707,655, and Nakamichi etal., U.S. Pat. No. 5,456,923.

[0007] Curatolo et al., EP 0901786A2, disclose solid amorphousdispersions of poorly water soluble drugs and hydroxypropylmethylcellulose acetate succinate (HPMCAS). In one embodiment, HPMCAS is adispersion polymer. Alternatively, a dispersion may be formed of a drugand conventional matrix material such as PVP, HPC or HPMC and then thedispersion is triturated with HPMCAS.

[0008] One problem with using the amorphous form of a drug is that thesolid drug may not be stable physically in the amorphous form. Often thecrystalline form of the drug has a lower free energy, and thus overtime, the amorphous drug will tend to crystallize. The rate ofcrystallization may be influenced by storage conditions, such astemperature and humidity, as well as the constituents of thecomposition.

[0009] Similarly, even if a dispersion of drug and polymer is formed,the drug in the resulting amorphous dispersion of polymer and drug mayin some cases be unstable. For example, the dispersion may be physicallyunstable, causing the amorphous drug to separate from the dispersionand/or crystallize. Alternatively, the drug in the amorphous dispersionmay be chemically unstable. The drug may degrade over time at moderatetemperature and humidity levels or the drug may convert to a lowerenergy and lower solubility amorphous or crystalline form.

[0010] Alternatively, it may be difficult or, in some cases, impossibleto form a dispersion of the drug and preferred polymer. In particular,the drug and preferred polymer may not both be amenable to a processingmethod that results in a dispersion of the drug and preferred polymer.For example, when solvent processing is the preferred method for formingthe dispersion, the drug and preferred polymer may not both be solubleto a sufficient extent in an appropriate processing solvent to allowformation of the dispersion. In cases where melt processing ispreferred, the drug or polymer or both may suffer unacceptabledecomposition upon heating to allow the formation of the preferredcomposition to be practical.

[0011] Accordingly, what is still desired is a composition comprising anamorphous drug that is physically and/or chemically stable under typicalstorage conditions, may be formed via practical processing conditions,and that may enhance the bioavailability of poorly soluble drugs. Theseneeds and others that will become apparent to one of ordinary skill aremet by the present invention, which is summarized and described indetail below.

BRIEF SUMMARY OF THE INVENTION

[0012] The present invention, in one aspect, relates to pharmaceuticalcompositions comprising: (a) a solid dispersion comprising alow-solubility drug and a matrix, wherein at least a major portion ofsaid drug in said dispersion is amorphous; and (b) aconcentration-enhancing polymer, said dispersion being free from atleast a portion of said concentration-enhancing polymer; wherein saidcomposition provides improved stability of said drug relative to atleast one of a first control composition consisting of a mixture of saidlow-solubility drug in undispersed amorphous form and saidconcentration-enhancing polymer, and a second control compositionconsisting of a dispersion of said low-solubility drug and saidconcentration-enhancing polymer.

[0013] In a second aspect, the present invention relates topharmaceutical compositions comprising: (a) a solid dispersioncomprising a low-solubility drug and a matrix, wherein at least a majorportion of said drug in said dispersion is amorphous; and (b) aconcentration-enhancing polymer, said dispersion being free from atleast a portion of said concentration-enhancing polymer; wherein atleast 10 wt % of said matrix is non-polymeric.

[0014] In a third aspect, the present invention relates topharmaceutical compositions comprising: (a) a solid dispersioncomprising a low-solubility drug and a matrix, wherein at least a majorportion of said drug in said dispersion is amorphous; and (b) aconcentration-enhancing polymer, said dispersion being free from atleast a portion of said concentration-enhancing polymer; wherein saidconcentration-enhancing polymer is non-cellulosic.

[0015] In a fourth aspect, the present invention relates topharmaceutical compositions, comprising: (a) a solid dispersioncomprising a low-solubility drug and a matrix, wherein at least a majorportion of said drug in said dispersion is amorphous; and (b) aconcentration-enhancing polymer, said dispersion being free from atleast a portion of said concentration-enhancing polymer, wherein saidconcentration-enhancing polymer is selected from the group consisting ofnon-ionizable cellulosic polymers and neutralized acidic polymers.

[0016] In a fifth aspect, the present invention relates topharmaceutical compositions, comprising: (a) a solid dispersioncomprising a low-solubility drug and a matrix, wherein at least a majorportion of said drug in said dispersion is amorphous; and (b) aconcentration-enhancing polymer, said dispersion being free from atleast a portion of said concentration-enhancing polymer, wherein saidconcentration-enhancing polymer is an ionizable cellulosic polymerhaving at least one of an ester-linked carboxylic acid-functionalaromatic substituent and an ether-linked carboxylic acid-functionalaromatic substituent.

[0017] In a sixth aspect, the present invention relates topharmaceutical compositions, comprising: (a) a solid dispersioncomprising a low-solubility drug and a matrix, wherein at least a majorportion of said drug in said dispersion is amorphous; (b) anamphiphilic, cellulosic concentration-enhancing polymer, said dispersionbeing free from at least a portion of said amphiphilic, cellulosicconcentration-enhancing polymer; (c) said amphiphilic cellulosicconcentration-enhancing polymer having at least one hydrophobicsubstituent selected from the group consisting of ether-linked alkylsubstituents, ester-linked alkyl substituents, ether-linked arylsubstituents and ester-linked aryl substituents; (d) said amphiphiliccellulosic concentration-enhancing polymer having at least onehydrophilic substituent selected from the group consisting ofether-linked hydroxy alkyl substituents, ester-linked hydroxy alkylsubstituents, alkyl ether groups, ester-linked ionizable substituents,and ether-linked ionizable substituents; and (e) provided that when saidconcentration-enhancing polymer has both the hydrophilic substituentshydroxypropyl and succinate, said polymer is free from both anether-linked methyl substituent and an ester-linked acetate substituent.

[0018] In a preferred embodiment, the drug has improved physicalstability in said composition relative to said first controlcomposition.

[0019] In another preferred embodiment, at least a major portion of saiddrug is dissolved in said matrix.

[0020] In another preferred embodiment, the drug has a solubility insaid matrix that is at least 30% of a concentration of said drug in saidmatrix.

[0021] In another preferred embodiment, the drug has a weight ratio tosaid matrix of said dispersion of less than 20.

[0022] In yet another preferred embodiment, the dispersion has a glasstransition temperature that is greater than a glass transitiontemperature of at least one of said low-solubility drug in undispersedamorphous form and said second control composition.

[0023] In another preferred embodiment, the dispersion has a glasstransition temperature that is greater than about 50° C. at 50% relativehumidity.

[0024] In another preferred embodiment, the drug in said dispersion hasa crystallization rate that is less than 90% of a crystallization rateof said drug in undispersed amorphous form.

[0025] In another preferred embodiment, the drug in said composition hasa relative degree of improvement in chemical stability of at least 1.25relative to at least one of said first control composition and saidsecond control composition.

[0026] In still another preferred embodiment, the drug is acid-sensitiveand said concentration-enhancing polymer is acidic.

[0027] In another preferred embodiment, the drug in said composition hasimproved stability, preferably improved physical stability, relative toat least one of a first control composition consisting of a mixture ofsaid low-solubility drug in undispersed amorphous form and saidconcentration-enhancing polymer, and a second control compositioncomprising a dispersion of said drug and said concentration-enhancingpolymer.

[0028] In another preferred embodiment, at least 10 wt % of said matrixis non-polymeric. Preferred components of said matrix are selected fromthe group consisting of alcohols, organic acids, organic bases, aminoacids, sugars, fatty acid esters, alkyl sulfates, phospholipids, waxesand salts.

[0029] In yet another preferred embodiment, the matrix has at least onepolymeric component. Preferred components of said matrix are selectedfrom the group consisting of polyethylene glycols, polyoxyethyleneglycols, polyethylene-polypropylene glycol copolymers, polyethyleneoxides, polyvinylpyrrolidone, polyvinyl alcohols, polyethylene-vinylalcohol copolymers, polyvinyl alcohol polyvinyl acetate copolymers,carboxylic acid-functionalized polymethacrylates, amine-functionalizedpolymethacrylates, proteins, xanthan gum, carrageenan, hydroxypropylcellulose, hydroxypropyl methyl cellulose, carboxy methyl cellulose,chitosan, chitin, polydextrose, dextrin and starch.

[0030] In another preferred embodiment, the drug is substantiallyamorphous in said dispersion.

[0031] In another preferred embodiment, the dispersion is substantiallyhomogeneous.

[0032] In another preferred embodiment, the dispersion is completelyhomogeneous.

[0033] In another preferred embodiment, the composition is a solidmixture in which said concentration-enhancing polymer is suspended as aseparate phase within said dispersion.

[0034] In another preferred embodiment, the composition is a mixture ofparticles of dispersion and particles of concentration-enhancingpolymer.

[0035] In another preferred embodiment, the mixture is formed by atleast one of dry-granulation and wet-granulation.

[0036] In another preferred embodiment, the dispersion and saidconcentration-enhancing polymer are each in separate regions.

[0037] In another preferred embodiment, the compositions furthercomprise a blend of concentration-enhancing polymers selected from thegroup consisting of ionizable cellulosic polymers, non-ionizablecellulosic polymers, ioniziable non-cellulosic polymers, non-ionizablenon-cellulosic polymers, and neutralized acidic polymers.

[0038] In still another preferred embodiment, theconcentration-enhancing polymer has a hydrophobic portion and ahydrophilic portion.

[0039] In another preferred embodiment, the concentration-enhancingpolymer is an ionizable cellulosic polymer such as polymers selectedfrom the group consisting of hydroxypropyl methyl cellulose succinate,cellulose acetate succinate, methyl cellulose acetate succinate, ethylcellulose acetate succinate, hydroxypropyl cellulose acetate succinate,hydroxypropyl methyl cellulose acetate succinate, hydroxypropylcellulose acetate phthalate succinate, cellulose propionate succinate,hydroxypropyl cellulose butyrate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, methyl celluloseacetate phthalate, ethyl cellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, hydroxypropyl methyl cellulose acetatephthalate, cellulose propionate phthalate, hydroxypropyl cellulosebutyrate phthalate, cellulose acetate trimellitate, methyl celluloseacetate trimellitate, ethyl cellulose acetate trimellitate,hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate trimellitate, hydroxypropyl cellulose acetatetrimellitate succinate, cellulose propionate trimellitate, cellulosebutyrate trimellitate, cellulose acetate terephthalate, celluloseacetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylicacid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate,ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acidcellulose acetate, ethyl phthalic acid cellulose acetate, ethylnicotinic acid cellulose acetate, ethyl picolinic acid celluloseacetate, carboxy methyl cellulose, carboxy ethyl cellulose, ethylcarboxy methyl cellulose, and blends thereof. More preferably, theconcentration-enhancing polymer is selected from the group consisting ofhydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, and cellulose acetatetrimellitate, and blends thereof.

[0040] In another preferred embodiment, the concentration-enhancingpolymer is a non-ionizable cellulosic polymer, such as polymers selectedfrom the group consisting of hydroxypropyl methyl cellulose acetate,hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl methyl cellulose, hydroxyethyl celluloseacetate, and hydroxyethyl ethyl cellulose, and blends thereof.

[0041] In another preferred embodiment, the concentration-enhancingpolymer is an ionizable, non-cellulosic polymer, such as polymersselected from the group consisting of carboxylic acid functionalizedpolymethacrylates, carboxylic acid functionalized polyacrylates,amine-functionalized polyacrylates, amine-fuctionalizedpolymethacrylates, proteins, and carboxylic acid functionalizedstarches, and blends thereof.

[0042] In another preferred embodiment, the concentration-enhancingpolymer is a non-ionizable, non-cellulosic polymer such as polymersselected from the group consisting of vinyl polymers and copolymershaving at least one substituent selected from the group consisting ofhydroxyl, alkylacyloxy, and cyclicamido; vinyl copolymers of at leastone hydrophilic, hydroxyl-containing repeat unit and at least onehydrophobic, alkyl- or aryl-containing repeat unit; polyvinyl alcoholsthat have at least a portion of their repeat units in the unhydrolyzedform, polyvinyl alcohol polyvinyl acetate copolymers, polyethyleneglycol polypropylene glycol copolymers, polyvinyl pyrrolidone, andpolyethylene polyvinyl alcohol copolymers, and blends thereof.

[0043] In yet another preferred embodiment, the concentration-enhancingpolymer is selected from the group consisting of hydroxypropyl celluloseacetate phthalate succinate, hydroxypropyl methyl cellulose phthalate,cellulose acetate phthalate, methyl cellulose acetate phthalate, ethylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate,hydroxypropyl methyl cellulose acetate phthalate, cellulose propionatephthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetatetrimellitate, methyl cellulose acetate trimellitate, ethyl celluloseacetate trimellitate, hydroxypropyl cellulose acetate trimellitate,hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate succinate, cellulose propionatetrimellitate, cellulose butyrate trimellitate, cellulose acetateterephthalate, cellulose acetate isophthalate, cellulose acetatepyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropylsalicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate,hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acidcellulose acetate, ethyl nicotinic acid cellulose acetate, ethylpicolinic acid cellulose acetate, carboxy methyl cellulose, carboxyethyl cellulose, ethyl carboxy methyl cellulose, and blends thereof.

[0044] In another preferred embodiment, the amphiphilic, cellulosicconcentration-enhancing polymer is selected from the group consisting ofhydroxypropyl cellulose acetate succinate, hydroxypropyl methylcellulose, hydroxypropyl methyl cellulose acetate, hydroxypropyl methylcellulose succinate, hydroxypropyl methyl cellulose phthalate,hydroxypropyl methyl cellulose acetate phthalate, hydroxyethyl methylcellulose, hydroxyethyl methyl cellulose succinate, hydroxyethylcellulose acetate succinate, hydroxyethyl methyl cellulose acetatesuccinate, hydroxyethyl methyl cellulose acetate phthalate, hydroxyethylcellulose acetate, hydroxyethyl ethyl cellulose, carboxymethyl ethylcellulose, cellulose acetate phthalate, hydroxypropyl cellulose acetatephthalate, methyl cellulose acetate phthalate, ethyl cellulose acetatephthalate, hydroxypropyl cellulose acetate phthalate succinate,cellulose propionate phthalate, hydroxypropyl cellulose butyratephthalate, cellulose acetate trimellitate, methyl cellulose acetatetrimellitate, ethyl cellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate, hydroxypropyl methyl cellulose acetatetrimellitate, hydroxypropyl cellulose acetate trimellitate succinate,cellulose propionate trimellitate, cellulose butyrate trimellitate,cellulose acetate terephthalate, cellulose acetate isophthalate,cellulose acetate pyridinedicarboxylate, salicylic acid celluloseacetate, hydroxypropyl salicylic acid cellulose acetate, ethylbenzoicacid cellulose acetate, hydroxypropyl ethylbenzoic acid celluloseacetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic acidcellulose acetate, and ethyl picolinic acid cellulose acetate, andblends thereof.

[0045] In still another preferred embodiment, at least a portion of saidconcentration-enhancing polymer is neutralized. In other preferredembodiments, concentration-enhancing polymer is a neutralized acidicpolymer.

[0046] In still another preferred embodiment, the composition whenadministered to a use environment provides a dissolution area under theconcentration versus time curve for a time period of at least 90 minutesduring the 270 minutes immediately following introduction to said useenvironment that is at least 1.25-fold the corresponding area under thecurve provided by a control composition comprising an equivalent amountof undispersed amorphous drug alone.

[0047] In another preferred embodiment, the composition whenadministered to a use environment provides a maximum concentration ofsaid drug in said use environment that is at least 1.25-fold a maximumconcentration of said drug provided by a control composition comprisingan equivalent amount of undispersed amorphous drug alone.

[0048] In another preferred embodiment, the composition whenadministered to an animal provides a relative bioavailability of atleast 1.25 relative to a control composition comprising an equivalentamount of undispersed amorphous drug alone.

[0049] In another preferred embodiment, the composition whenadministered to a use environment provides a dissolution area under theconcentration versus time curve for a time period of at least 90 minutesduring the 270 minutes immediately following introduction to said useenvironment that is at least 1.25-fold the corresponding area under thecurve provided by a control composition comprising an equivalent amountof said dispersion but with no concentration-enhancing polymer.

[0050] In another preferred embodiment, the composition whenadministered to a use environment provides a maximum concentration ofsaid drug in said use environment that is at least 1.25-fold a maximumconcentration of said drug provided by a control composition comprisingan equivalent amount of said dispersion but with noconcentration-enhancing polymer.

[0051] In another preferred embodiment, the composition whenadministered to an animal provides a relative bioavailability of atleast 1.25 relative to a control composition comprising an equivalentamount of said dispersion but with no concentration-enhancing polymer.

[0052] In another preferred embodiment, the drug is selected from thegroup consisting of antihypertensives, antianxiety agents, anticlottingagents, anticonvulsants, blood glucose-lowering agents, decongestants,antihistamines, antitussives, antineoplastics, beta blockers,anti-inflammatories, antipsychotic agents, cognitive enhancers,cholesterol-reducing agents, antiobesity agents, autoimmune disorderagents, anti-impotence agents, antibacterial and antifungal agents,hypnotic agents, anti-Parkinsonism agents, anti-Alzheimer's diseaseagents, antibiotics, anti-depressants, antiviral agents,anti-atherosclerotic agents, glycogen phosphorylase inhibitors, andcholesterol ester transfer protein inhibitors.

[0053] In another preferred embodiment, the drug is a glycogenphosphorylase inhibitor selected from the group consisting of[R-(R′S′)]-5-chloro-N-[2-hydroxy-3-{methoxymethylamino}-3-oxo-1-(phenylmethyl)propyl-1H-indole-2-carboxamideand 5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide.

[0054] In another preferred embodiment, the drug is a cholesterol estertransfer protein inhibitor selected from the group consisting of[2R,4S]-4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester,[2R,4S]-4-[3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester, and [2R, 4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

[0055] In a seventh aspect, the present invention relates to methods ofadministering a drug comprising co-administering to a patient in need ofsaid drug: (a) a solid dispersion comprising a low-solubility drug and amatrix, wherein at least a major portion of said drug in said dispersionis amorphous; and (b) a concentration-enhancing polymer, said dispersionbeing free from at least a portion of said concentration-enhancingpolymer; wherein said dispersion provides improved stability of saiddrug relative to at least one of a first control composition consistingof a mixture of said low-solubility drug in undispersed amorphous formand said concentration-enhancing polymer, and a second controlcomposition consisting of a dispersion of said low-solubility drug andsaid concentration-enhancing polymer.

[0056] In a preferred embodiment, the dispersion is administeredseparately from said concentration-enhancing polymer.

[0057] In another preferred embodiment, the dispersion and saidconcentration-enhancing polymer are administered at approximately thesame time.

[0058] In another preferred embodiment, the dispersion and saidconcentration-enhancing polymer are present in a single dosage form.

[0059] The present invention also relates to, in an eighth aspect,methods of administering a drug comprising co-administering to a patientin need of said drug: (a) a solid dispersion comprising a low-solubilitydrug and a matrix, wherein at least a major portion of said drug in saiddispersion is amorphous; and (b) a concentration-enhancing polymer, saiddispersion being free from at least a portion of saidconcentration-enhancing polymer;

[0060] wherein at least 10 wt % of said matrix is non-polymeric.

[0061] In a ninth aspect, the present invention relates to methods ofadministering a drug comprising co-administering to a patient in need ofsaid drug: (a) a solid dispersion comprising a low-solubility drug and amatrix, wherein at least a major portion of said drug in said dispersionis amorphous; and (b) a concentration-enhancing polymer, said dispersionbeing free from at least a portion of said concentration-enhancingpolymer; wherein said concentration-enhancing polymer is non-cellulosic.

[0062] In a tenth aspect, the present invention relates to methods ofadministering a drug comprising co-administering to a patient in need ofsaid drug: (a) a solid dispersion comprising a low-solubility drug and amatrix, wherein at least a major portion of said drug in said dispersionis amorphous; and (b) a concentration-enhancing polymer, said dispersionbeing free from at least a portion of said concentration-enhancingpolymer, wherein said concentration-enhancing polymer is selected fromthe group consisting of non-ionizable cellulosic polymers andneutralized acidic polymers.

[0063] In an eleventh aspect, the present invention relates to methodsof administering a drug comprising co-administering to a patient in needof said drug: (a) a solid dispersion comprising a low-solubility drugand a matrix, wherein at least a major portion of said drug in saiddispersion is amorphous; and (b) a concentration-enhancing polymer, saiddispersion being free from at least a portion of saidconcentration-enhancing polymer, wherein said concentration-enhancingpolymer is an ionizable cellulosic polymer having at least one of anester-linked carboxylic acid-functional aromatic substituent and anether-linked carboxylic acid-functional aromatic substituent.

[0064] In a twelveth aspect, the present invention relates to methods ofadministering a drug comprising co-administering to a patient in need ofsaid drug: (a) a solid dispersion comprising a low-solubility drug and amatrix, wherein at least a major portion of said drug in said dispersionis amorphous; (b) an amphiphilic, cellulosic concentration-enhancingpolymer, said dispersion being free from at least a portion of saidamphiphilic, cellulosic concentration-enhancing polymer; (c) saidamphiphilic cellulosic concentration-enhancing polymer having at leastone hydrophobic substituent selected from the group consisting ofether-linked alkyl substituents, ester-linked alkyl substituents,ether-linked aryl substituents and ester-linked aryl substituents; (d)said amphiphilic cellulosic concentration-enhancing polymer having atleast one hydrophilic substituent selected from the group consisting ofether-linked hydroxy alkyl substituents, ester-linked hydroxy alkylsubstituents, alkyl ether substituents, ester-linked ionizablesubstituents, and ether-linked ionizable substituents; and (e) providedthat when said concentration-enhancing polymer has both the hydrophilicsubstituents hydroxypropyl and succinate, said polymer is free from bothan ether-linked methyl group and an ester-linked acetate group.

[0065] The solid compositions of the present invention are combinationscomprising (1) a dispersion of a low-solubility drug and matrix and (2)concentration-enhancing polymer(s). “Combination” as used herein meansthat the drug/matrix dispersion and concentration-enhancing polymer maybe in physical contact with each other or in close proximity but are notmixed at the molecular level so as to form a solid molecular dispersion.In other words, although the drug/matrix dispersion and theconcentration-enhancing polymer may be mixed, they remain as separatephases retaining their own physical properties such as melting points orglass-transition temperatures. Thus, the dispersion of the drug andmatrix is free from at least a portion, if not all, of theconcentration-enhancing polymer.

[0066] Alternatively, the drug/matrix dispersion andconcentration-enhancing polymer may be co-administered to a patient inneed of the drug. The dispersion and concentration-enhancing polymer maybe administered in separate or the same dosage forms, and may also beadministered at essentially the same time or at different times.

[0067] The present invention achieves its advantages by combining adispersed amorphous drug with a concentration-enhancing polymer. One keyto the present invention was the recognition by the inventors that theinitially enhanced concentration of the drug in solution provided by theamorphous drug could be maintained, and in some cases enhanced by theinteraction of the drug and concentration-enhancing polymer beingpresent together in the use environment. Thus, without implying anyparticular mechanism of action, it is believed that theconcentration-enhancing polymers of this invention may be viewed asacting as crystallization or precipitation inhibitors. In some cases,the concentration-enhancing polymers may also interact to form varioustypes of polymer-drug assemblies such as aggregates or colloids.Surprisingly, this may be accomplished by simply combining theconcentration-enhancing polymer with the dispersion, in contrast toforming a molecular dispersion of the drug, matrix andconcentration-enhancing polymer.

[0068] Regardless of the mechanism, the compositions provide improvedconcentration of drug in the use environment. The drug/matrixdispersion, when introduced to a use environment, provides an initialconcentration of drug that exceeds the equilibrium concentration ofdrug, while the concentration-enhancing polymer retards the rate atwhich the initially enhanced drug concentration falls to the equilibriumconcentration. Thus, the compositions of the present invention provide adissolution area-under-the-concentration-versus-time-curve (“AUC”) thatis greater than that provided by crystalline drug alone. In preferredembodiments, the compositions of the present invention provide an AUCthat is greater than that provided by either the drug/matrix dispersionitself or by the drug in undispersed amorphous form andconcentration-enhancing polymer.

[0069] Preferably, the compositions provide a maximum drug concentrationthat exceeds the maximum drug concentration provided by either a controlconsisting of the dispersion itself or by a control consisting of theundispersed amorphous drug plus concentration-enhancing polymer.Nevertheless, the advantages of the invention may be obtained by merelyretarding the rate at which the enhanced drug concentration falls to theequilibrium concentration, even without increasing the maximum drugconcentration relative to a control composition.

[0070] As a result of improving the dissolution AUC, the compositions ofthe present invention may also provide enhanced bioavailability of thedrug by increasing the concentration of drug which remains dissolved inthe use environment, particularly in the GI tract. Improving theconcentration of the drug in solution allows more rapid absorption ofdrug and, as a result, higher blood levels to be achieved. In some casesthis enhanced absorption rate enables an effective level of drug to bereached that might not be reached by administration of conventionalforms of the drug. In other cases, administration of the compositions ofthe invention allows effective blood levels to be reached at lower drugdosage levels, which in turn decreases the amount of drug that must bedosed, and reduces the blood level variability. Such compositions mayalso allow the size of the dosage form to be decreased, depending on theamount of polymer needed.

[0071] Furthermore, because the compositions of the present inventionprovide for a higher concentration of drug dissolved in the useenvironment, and because once a high drug concentration is achieved theconcentration tends to remain high due to inhibition of precipitation orcrystallization of the drug, the compositions may have a number ofpositive effects. First, in cases where the use environment is the GItract, the compositions of the present invention may show lessvariability in drug absorption as a result of variation in thefed/fasted state of the GI tract of the human or animal. Second, due toa prolonged high drug concentration in the GI tract, absorption of drugmay continue over a longer time period and an effective concentration ofdrug in the blood may be maintained over a longer time period.

[0072] Stabilizing the drug in a dispersion of the drug and matrix andthen combining the dispersion with the concentration-enhancing polymerprovides another of the advantages of the present invention, which is toallow the use of concentration-enhancing polymers which, for whateverreason, are not suitable for forming a molecular dispersion with theparticular drug. In one embodiment, the invention solves the problempresented where it is difficult to combine the preferredconcentration-enhancing polymer and drug to form a stable moleculardispersion. The difficulty in forming a stable dispersion may be due toadverse interactions between the drug and polymer in the dispersion,resulting in chemical and/or physical instability of the drug in thedispersion. For example, although an acidic cellulosic polymer mayprovide superior concentration-enhancement for some drugs, such polymersmay chemically degrade acid-sensitive drugs when present in thedispersion.

[0073] Alternatively, the preferred concentration-enhancing polymer maynot be amenable to the preferred process used to form dispersions of thedrug. For example, cellulosic polymers do not readily melt, and thus arenot suitable for use in forming dispersions of drug and the cellulosicpolymer by use of most melt-fusion processes. As another example, themobility of polymers having a high glass transition temperature is toolow to allow use of mechanical processes, such as ball milling, to formdispersions. Alternatively, the drug and concentration-enhancing polymermay not share a common solvent, thus precluding the formation of adispersion of the drug and concentration-enhancing polymer using solventprocessing.

[0074] The present invention solves these problems by forming anamorphous dispersion of the drug in an alternative matrix material toform a drug/matrix dispersion, and then combines the drug/matrixdispersion with the concentration-enhancing polymer to form thecomposition. This provides the benefit of either improved drug stabilityor use of a preferred processing method while at the same time providingthe additional level of concentration-enhancement conferred by thepresence of the concentration-enhancing polymer.

[0075] The foregoing and other objectives, features, and advantages ofthe invention will be more readily understood upon consideration of thefollowing detailed description of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0076] The present invention provides in one aspect a compositioncomprising (1) a solid dispersion comprising a low-solubility drug andmatrix, wherein at least a major portion of the drug in the dispersionis amorphous and (2) a concentration-enhancing polymer, wherein the drugin the composition has improved chemical or physical stability relativeto an appropriate control composition. In another aspect, the inventioncomprises (1) a solid dispersion comprising a low-solubility drug and amatrix, wherein at least a major portion of the drug in the dispersionis amorphous and (2) a concentration-enhancing polymer, wherein theconcentration-enhancing polymer is present in a sufficient amount sothat the composition improves the concentration of the drug in a useenvironment relative to an appropriate control composition. In yetanother aspect, the invention provides a method for co-administering (1)a solid amorphous dispersion comprising a low-solubility drug and amatrix, and (2) a concentration-enhancing polymer. Suitable drug(s),matrices, and concentration-enhancing polymer(s), as well as methods forpreparing the compositions, are discussed in detail below.

The Drug

[0077] The present invention is useful with any drug capable of beingformulated as an amorphous drug. The term “drug” is conventional,denoting a compound having beneficial prophylactic and/or therapeuticproperties when administered to an animal, especially humans. The drugdoes not need to be a low-solubility drug in order to benefit from thisinvention, although low-solubility drugs represent a preferred class foruse with the invention. Even a drug that nonetheless exhibitsappreciable solubility in the desired environment of use can benefitfrom the increased solubility/bioavailability made possible by thisinvention if the addition of the concentration-enhancing polymer canreduce the size of the dose needed for therapeutic efficacy or increasethe rate of drug absorption in cases where a rapid onset of the drug'seffectiveness is desired.

[0078] Preferably, the drug is a “low-solubility drug,” meaning that thedrug may be either “substantially water-insoluble,” which means that thedrug has a minimum aqueous solubility at physiologically relevant pH(e.g., pH 1-8) of less than 0.01 mg/mL, “sparingly water-soluble,” thatis, has an aqueous solubility up to about 1 to 2 mg/mL, or even low tomoderate aqueous-solubility, having an aqueous-solubility from about 1mg/mL to as high as about 20 to 40 mg/mL. The invention finds greaterutility as the solubility of the drug decreases. Thus, compositions ofthe present invention are preferred for low-solubility drugs having asolubility of less than 10 mg/mL, more preferred for low-solubilitydrugs having a solubility of less than 1 mg/mL, and even more preferredfor low-solubility drugs having a solubility of less than 0.1 mg/mL. Ingeneral, it may be said that the drug has a dose-to-aqueous solubilityratio greater than 10 mL, and more typically greater than 100 mL, wherethe drug solubility (mg/mL) is the minimum value observed in anyphysiologically relevant aqueous solution (e.g., those with pH valuesbetween 1 and 8) including USP simulated gastric and intestinal buffers,and the dose is in mg. Thus, a dose-to-aqueous-solubility ratio may becalculated by dividing the dose (in mg) by the solubility (in mg/mL).

[0079] Preferred classes of drugs include, but are not limited to,antihypertensives, antianxiety agents, anticlotting agents,anticonvulsants, blood glucose-lowering agents, decongestants,antihistamines, antitussives, antineoplastics, beta blockers,anti-inflammatories, antipsychotic agents, cognitive enhancers,anti-atherosclerotic agents, cholesterol-reducing agents, antiobesityagents, autoimmune disorder agents, anti-impotence agents, antibacterialand antifungal agents, hypnotic agents, anti-Parkinsonism agents,anti-Alzheimer's disease agents, antibiotics, anti-depressants,antiviral agents, glycogen phosphorylase inhibitors, and cholesterolester transfer protein inhibitors.

[0080] Each named drug should be understood to include the neutral formof the drug, pharmaceutically acceptable salts, as well as prodrugs.Specific examples of antihypertensives include prazosin, nifedipine,amlodipine besylate, trimazosin and doxazosin; specific examples of ablood glucose-lowering agent are glipizide and chlorpropamide; aspecific example of an anti-impotence agent is sildenafil and sildenafilcitrate; specific examples of antineoplastics include chlorambucil,lomustine and echinomycin; a specific example of an imidazole-typeantineoplastic is tubulazole; a specific example of ananti-hypercholesterolemic is atorvastatin calcium; specific examples ofanxiolytics include hydroxyzine hydrochloride and doxepin hydrochloride;specific examples of anti-inflammatory agents include betamethasone,prednisolone, aspirin, piroxicam, valdecoxib, carprofen, celecoxib,flurbiprofen and(+)-N-{4-[3-(4-fluorophenoxy)phenoxy]-2-cyclopenten-1-yl}-N-hyroxyurea;a specific example of a barbiturate is phenobarbital; specific examplesof antivirals include acyclovir, nelfinavir, and virazole; specificexamples of vitamins/nutritional agents include retinol and vitamin E;specific examples of beta blockers include timolol and nadolol; aspecific example of an emetic is apomorphine; specific examples of adiuretic include chlorthalidone and spironolactone; a specific exampleof an anticoagulant is dicumarol; specific examples of cardiotonicsinclude digoxin and digitoxin; specific examples of androgens include17-methyltestosterone and testosterone; a specific example of a mineralcorticoid is desoxycorticosterone; a specific example of a steroidalhypnotic/anesthetic is alfaxalone; specific examples of anabolic agentsinclude fluoxymesterone and methanstenolone; specific examples ofantidepression agents include sulpiride,[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethylpropyl)-amine,3,5-dimethyl-4-(3′-pentoxy)-2-(2′,4′,6′-trimethylphenoxy)pyridine,pyroxidine, fluoxetine, paroxetine, venlafaxine and sertraline; specificexamples of antibiotics include carbenicillin indanylsodium,bacampicillin hydrochloride, troleandomycin, doxycyline hyclate,ampicillin and penicillin G; specific examples of anti-infectivesinclude benzalkonium chloride and chlorhexidine; specific examples ofcoronary vasodilators include nitroglycerin and mioflazine; a specificexample of a hypnotic is etomidate; specific examples of carbonicanhydrase inhibitors include acetazolamide and chlorzolamide; specificexamples of antifungals include econazole, terconazole, fluconazole,voriconazole, and griseofulvin; a specific example of an antiprotozoalis metronidazole; specific examples of anthelmintic agents includethiabendazole and oxfendazole and morantel; specific examples ofantihistamines include astemizole, levocabastine, cetirizine,decarboethoxyloratadine, and cinnarizine; specific examples ofantipsychotics include ziprasidone, olanzepine, thiothixenehydrochloride, fluspirilene, risperidone and penfluridole; specificexamples of gastrointestinal agents include loperamide and cisapride;specific examples of serotonin antagonists include ketanserin andmianserin; a specific example of an anesthetic is lidocaine; a specificexample of a hypoglycemic agent is acetohexamide; a specific example ofan anti-emetic is dimenhydrinate; a specific example of an antibacterialis cotrimoxazole; a specific example of a dopaminergic agent is L-DOPA;specific examples of anti-Alzheimer's Disease agents are THA anddonepezil; a specific example of an anti-ulcer agent/H2 antagonist isfamotidine; specific examples of sedative/hypnotic agents includechlordiazepoxide and triazolam; a specific example of a vasodilator isalprostadil; a specific example of a platelet inhibitor is prostacyclin;specific examples of ACE inhibitor/antihypertensive agents includeenalaprilic acid and lisinopril; specific examples of tetracyclineantibiotics include oxytetracycline and minocycline; specific examplesof macrolide antibiotics include erythromycin, clarithromycin, andspiramycin; a specific example of an azalide antibiotic is azithromycin;specific examples of glycogen phosphorylase inhibitors include[R-(R′S′)]-5-chloro-N-[2-hydroxy-3-{methoxymethylamino}-3-oxo-1-(phenylmethyl)propyl-1H-indole-2-carboxamideand 5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide;and specific examples of cholesterol ester transfer protein (CETP)inhibitors include [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester, [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester, [2R, 4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

[0081] The invention is not limited by any particular structure or groupof CETP inhibitors. Rather, the invention has general applicability toCETP inhibitors as a class, the class tending to be composed ofcompounds having low solubility. Compounds which may be the subject ofthe invention may be found in a number of patents and publishedapplications, including DE 19741400 A1; DE 19741399 A1; WO 9914215 A1;WO 9914174; DE 19709125 A1; DE 19704244 A1; DE 19704243 A1; EP 818448A1; WO 9804528 A2; DE 19627431 A1; DE 19627430 A1; DE 19627419 A1; EP796846 A1; DE 19832159; DE 818197; DE 19741051; WO 9941237 A1; WO9914204 A1; WO 9835937 A1; JP 11049743; WO 200018721; WO 200018723; WO200018724; WO 200017164; WO 200017165; WO 200017166; EP 992496; and EP987251, all of which are hereby incorporated by reference in theirentireties for all purposes.

[0082] The invention is useful for CETP inhibitors that havesufficiently low aqueous solubility, low bioavailability or slow rate ofabsorption such that it is desirable to increase their concentration inan aqueous environment of use. Therefore, anytime one finds it desirableto raise the aqueous concentration of the CETP inhibitor in a useenvironment, the invention will find utility. The CETP inhibitor is“substantially water-insoluble” which means that the CETP inhibitor hasa minimum aqueous solubility of less than about 0.01 mg/mL (or 10 μg/ml)at any physiologically relevant pH (e.g., pH 1-8) and at about 22° C.(Unless otherwise specified, reference to aqueous solubility herein andin the claims is determined at about 22° C.) Compositions of the presentinvention find greater utility as the solubility of the CETP inhibitorsdecreases, and thus are preferred for CETP inhibitors with solubilitiesless than about 2 μg/mL, and even more preferred for CETP inhibitorswith solubilities less than about 0.5 μg/mL. Many CETP inhibitors haveeven lower solubilities (some even less than 0.1 μg/mL), and requiredramatic concentration enhancement to be sufficiently bioavailable uponoral dosing for effective plasma concentrations to be reached atpractical doses.

[0083] In general, it may be said that the CETP inhibitor has adose-to-aqueous solubility ratio greater than about 100 mL, where thesolubility (mg/mL) is the minimum value observed in any physiologicallyrelevant aqueous solution (e.g., those with pH values from 1 to 8)including USP simulated gastric and intestinal buffers, and dose is inmg. Compositions of the present invention, as mentioned above, findgreater utility as the solubility of the CETP inhibitor decreases andthe dose increases. Thus, the compositions are preferred as thedose-to-solubility ratio increases, and thus are preferred fordose-to-solubility ratios greater than 1000 mL, and more preferred fordose-to-solubility ratios greater than about 5000 ml. Thedose-to-solubility ratio may be determined by dividing the dose (in mg)by the aqueous solubility (in mg/ml).

[0084] Oral delivery of many CETP inhibitors is particularly difficultbecause their aqueous solubility is usually extremely low, typicallybeing less than 2 μg/ml, often being less than 0.1 μg/ml. Such lowsolubilities are a direct consequence of the particular structuralcharacteristics of species that bind to CETP and thus act as CETPinhibitors. This low solubility is primarily due to the hydrophobicnature of CETP inhibitors. Clog P, defined as the base 10 logarithm ofthe ratio of the drug solubility in octanol to the drug solubility inwater, is a widely accepted measure of hydrophobicity. In general, ClogP values for CETP inhibitors are greater than 4 and are often greaterthan 5 to 7. Thus, the hydrophobic and insoluble nature of CETPinhibitors as a class pose a particular challenge for oral delivery.Achieving therapeutic drug levels in the blood by oral dosing ofpractical quantities of drug generally requires a large enhancement indrug concentrations in the gastrointestinal fluid and a resulting largeenhancement in bioavailability. Such enhancements in drug concentrationin gastrointestsinal fluid typically need to be at least about 10-foldand often at least about 50-fold or even at least about 200-fold toachieve desired blood levels. Surprisingly, the dispersions of thepresent invention have proven to have the required large enhancements indrug concentration and bioavailability.

[0085] In contrast to conventional wisdom, the relative degree ofenhancement in aqueous concentration and bioavailability generallyimproves for CETP inhibitors as solubility decreases and hydrophobocityincreases. In fact, the inventors have recognized a subclass of theseCETP inhibitors that are essentially aqueous insoluble, highlyhydrophobic, and are characterized by a set of physical properties. Thissubclass exhibits dramatic enhancements in aqueous concentration andbioavailability when formulated using the compositions of the presentinvention.

[0086] The first property of this subclass of essentially insoluble,hydrophobic CETP inhibitors is extremely low aqueous solubility. Byextremely low aqueous solubility is meant that the minimum aqueoussolubility at physiologically relevant pH (pH of 1 to 8) is less thanabout 10 μg/ml and preferably less than about 1 μg/ml.

[0087] A second property is a very high does-to-solubility ratio.Extremely low solubility often leads to poor or slow absorption of thedrug from the fluid of the gastrointestinal tract, when the drug isdosed orally in a conventional manner. For extremely low solubilitydrugs, poor absorption generally becomes progressively more difficult asthe dose (mass of drug given orally) increases. Thus, a second propertyof this subclass of essentially insoluble, hydrophobic CETP inhibitorsis a very high dose (in mg) to solubility (in mg/ml) ratio (ml). By“very high dose-to-solubility ratio” is meant that thedose-to-solubility ratio has a value of at least 1000 ml, and preferablyat least 5,000 ml, and more preferably at least 10,000 ml.

[0088] A third property of this subclass of essentially insoluble,hydrophobic CETP inhibitors is that they are extremely hydrophobic. Byextremely hydrophobic is meant that the Clog P value of the drug, has avalue of at least 4.0, preferably a value of at least 5.0, and morepreferably a value of at least 5.5.

[0089] A fourth property of this subclass of essentially insoluble CETPinhibitors is that they have a low melting point. Generally, drugs ofthis subclass will have a melting point of about 150° C. or less, andpreferably about 140° C. or less.

[0090] Primarily, as a consequence of some or all of these fourproperties, CETP inhibitors of this subclass typically have very lowabsolute bioavailabilities. Specifically, the absolute bioavailibilityof drugs in this subclass when dosed orally in their undispersed stateis less than about 10% and more often less than about 5%.

[0091] Turning now to the chemical structures of specific CETPinhibitors, one class of CETP inhibitors that finds utility with thepresent invention consists of oxy substituted4-carboxyamino-2-methyl-1,2,3,4-tetrahydroquinolines having the FormulaI

[0092] and pharmaceutically acceptable salts, enantiomers, orstereoisomers of said compounds;

[0093] wherein R_(I-1) is hydrogen, Y_(I), W_(I)-X_(I), W_(I)-Y_(I);

[0094] wherein W_(I) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

[0095] X_(I) is —O—Y_(I), —S—Y_(I), —N(H)—Y_(I) or —N—(Y_(I))₂;

[0096] wherein Y_(I) for each occurrence is independently Z_(I) or afully saturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(I);

[0097] wherein Z_(I) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0098] wherein said Z_(I) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxyl, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxyl,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; R_(I-3) is hydrogen or Q_(I);

[0099] wherein Q_(I) is a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono-, or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(I);

[0100] wherein V_(I) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0101] wherein said V_(I) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carbamoyl, mono-N- or di-N,N-(C₁-C₆) alkylcarbamoyl, carboxyl,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxyl,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are also optionallysubstituted with from one to nine fluorines;

[0102] R_(I-4) is Q_(I-1) or V_(I-1)

[0103] wherein Q_(I-1) is a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono-, or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with

[0104] V_(I-1);

[0105] wherein V_(I-1) is a partially saturated, fully saturated orfully unsaturated three to six membered ring optionally having one totwo heteroatoms selected independently from oxygen, sulfur and nitrogen;

[0106] wherein said V_(I-1) substituent is optionally mono-, di-, tri-,or tetra-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isalso optionally substituted with from one to nine fluorines;

[0107] wherein either R_(I-3) must contain V_(I) or R_(I-4) must containV_(I-1); and R_(I-5), R_(I-6), R_(I-7) and R_(I-8) are eachindependently hydrogen, hydroxy or oxy wherein said oxy is substitutedwith T_(I) or a partially saturated, fully saturated or fullyunsaturated one to twelve membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one or two heteroatoms selected independently from oxygen,sulfur and nitrogen and said carbon is optionally mono-, di- ortri-substituted independently with halo, said carbon is optionallymono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon chain is optionallymono-substituted with T_(I);

[0108] wherein T_(I) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0109] wherein said T_(I) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines.

[0110] Compounds of Formula I and their methods of manufacture aredisclosed in commonly assigned U.S. Pat. No. 6,140,342, U.S. Pat. No.6,362,198, and European Patent publication 987251, all of which areincorporated herein by reference in their entireties for all purposes.

[0111] In a preferred embodiment, the CETP inhibitor is selected fromone of the following compounds of Formula I:

[0112] [2R,4S]4-[(3,5-dichloro-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0113] [2R,4S]4-[(3,5-dinitro-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0114] [2R,4S]4-[(2,6-dichloro-pyridin-4-ylmethyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0115] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0116] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0117] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester,

[0118] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0119] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-ethoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0120] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid 2,2,2-trifluoro-ethylester;

[0121] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester;

[0122] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester;

[0123] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-trifluoromethoxy-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester,

[0124] [2R,4S] (3,5-bis-trifluoromethyl-benzyl)-(1-butyryl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamicacid methyl ester;

[0125] [2R,4S] (3,5-bis-trifluoromethyl-benzyl)-(1-butyl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamicacid methyl ester; and

[0126] [2R,4S] (3,5-bis-trifluoromethyl-benzyl)-[1-(2-ethyl-butyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-carbamicacid methyl ester, hydrochloride.

[0127] Another class of CETP inhibitors that finds utility with thepresent invention consists of4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines, having theFormula II

[0128] and pharmaceutically acceptable salts, enantiomers, orstereoisomers of said compounds;

[0129] wherein R_(II-1) is hydrogen, Y_(II), W_(II)—X_(II),W_(II)—Y_(II);

[0130] wherein W_(II) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

[0131] X_(II) is —O—Y_(II), —S—Y_(II), —N(H)—Y_(II) or —N—(Y_(II))₂;

[0132] wherein Y_(II) for each occurrence is independently Z_(II) or afully saturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(II);

[0133] Z_(II) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0134] wherein said Z_(II) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl is also optionally substituted with from one to ninefluorines;

[0135] R_(II-3) is hydrogen or Q_(II);

[0136] wherein Q_(II) is a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(II);

[0137] wherein V_(II) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0138] wherein said V_(II) substituent is optionally mono-, di-, tri-,or tetra-substituted independently with halo, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro,cyano, oxo, carboxamoyl, mono-N- or di-N,N-(C₁-C₆) alkylcarboxamoyl,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionallymono-, di- or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino or said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are optionally substitutedwith from one to nine fluorines;

[0139] R_(II-4) is Q_(II-1) or V_(II-1)

[0140] wherein Q_(II-1) a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(II-1);

[0141] wherein V_(II-1) is a partially saturated, fully saturated orfully unsaturated three to six membered ring optionally having one totwo heteroatoms selected independently from oxygen, sulfur and nitrogen;

[0142] wherein said V_(II-1) substituent is optionally mono-, di-, tri-,or tetra-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isoptionally substituted with from one to nine fluorines;

[0143] wherein either R_(II-3) must contain V_(II) or R_(II-4) mustcontain V_(II-1); and R_(II-5), R_(II-6), R_(II-7) and R_(II-8) are eachindependently hydrogen, a bond, nitro or halo wherein said bond issubstituted with T_(II) or a partially saturated, fully saturated orfully unsaturated (C₁-C₁₂) straight or branched carbon chain whereincarbon may optionally be replaced with one or two heteroatoms selectedindependently from oxygen, sulfur and nitrogen wherein said carbon atomsare optionally mono-, di- or tri-substituted independently with halo,said carbon is optionally mono-substituted with hydroxy, said carbon isoptionally mono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon is optionally mono-substitutedwith T_(II);

[0144] wherein T_(II) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0145] wherein said T_(II) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; provided that at least one of substituents R_(II-5),R_(II-6), R_(II-7) and R_(II-8) is not hydrogen and is not linked to thequinoline moiety through oxy.

[0146] Compounds of Formula II and their methods of manufacture aredisclosed in commonly assigned U.S. Pat. No. 6,147,090, U.S. patentapplication Ser. No. 09/671,400 filed Sep. 27, 2000, and PCT PublicationNo. WO00/17166, all of which are incorporated herein by reference intheir entireties for all purposes.

[0147] In a preferred embodiment, the CETP inhibitor is selected fromone of the following compounds of Formula II:

[0148] [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0149] [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0150] [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0151] [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2,6,7-trimethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0152] [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-diethyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0153] [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-ethyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0154] [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester; and

[0155] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

[0156] Another class of CETP inhibitors that finds utility with thepresent invention consists of annulated4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines, having theFormula III

[0157] and pharmaceutically acceptable salts, enantiomers, orstereoisomers of said compounds;

[0158] wherein R_(III-1) is hydrogen, Y_(III), W_(III)—X_(III),W_(III—Y) _(III);

[0159] wherein W_(III) is a carbonyl, thiocarbonyl, sulfinyl orsulfonyl;

[0160] X_(III) is —O—Y_(III), —S—Y_(III), —N(H)—Y_(III) or—N—(Y_(III))₂;

[0161] Y_(III) for each occurrence is independently Z_(III) or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(III);

[0162] wherein Z_(III) is a partially saturated, fully saturated orfully unsaturated three to twelve membered ring optionally having one tofour heteroatoms selected independently from oxygen, sulfur andnitrogen, or a bicyclic ring consisting of two fused partiallysaturated, fully saturated or fully unsaturated three to six memberedrings, taken independently, optionally having one to four heteroatomsselected independently from nitrogen, sulfur and oxygen;

[0163] wherein said Z_(III) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl optionally substituted with from one to nine fluorines;

[0164] R_(III-3) is hydrogen or Q_(III);

[0165] wherein Q_(III) is a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(III);

[0166] wherein V_(III) is a partially saturated, fully saturated orfully unsaturated three to twelve membered ring optionally having one tofour heteroatoms selected independently from oxygen, sulfur andnitrogen, or a bicyclic ring consisting of two fused partiallysaturated, fully saturated or fully unsaturated three to six memberedrings, taken independently, optionally having one to four heteroatomsselected independently from nitrogen, sulfur and oxygen;

[0167] wherein said V_(III) substituent is optionally mono-, di-, tri-,or tetra-substituted independently with halo, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro,cyano, oxo, carboxamoyl, mono-N- or di-N,N-(C₁-C₆) alkylcarboxamoyl,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionallymono-, di- or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino or said(C₁-C₆)alkyl or (C₂-C₆)alkenyl are optionally substituted with from oneto nine fluorines;

[0168] R_(III-4) is Q_(III-1) or V_(III-1);

[0169] wherein Q_(III-1) a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono- substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with

[0170] V_(III-1);

[0171] wherein V_(III-1) is a partially saturated, fully saturated orfully unsaturated three to six membered ring optionally having one totwo heteroatoms selected independently from oxygen, sulfur and nitrogen;

[0172] wherein said V_(III-1) substituent is optionally mono-, di-,tri-, or tetra-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituentoptionally having from one to nine fluorines;

[0173] wherein either R_(III-3) must contain V_(III) or R_(III-4) mustcontain V_(III-1); and R_(III-5) and R_(III-6), or R_(III-6) andR_(III-7), and/or R_(III-7) and R_(III-8) are taken together and form atleast one four to eight membered ring that is partially saturated orfully unsaturated optionally having one to three heteroatomsindependently selected from nitrogen, sulfur and oxygen;

[0174] wherein said ring or rings formed by R_(III-5) and R_(III-6), orR_(III-6) and R_(III-7), and/or R_(III-7) and R_(III-8) are optionallymono-, di- or tri-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent optionally having from one to nine fluorines;

[0175] provided that the R_(III-5), R_(III-6), R_(III-7) and/orR_(III-8), as the case may be, that do not form at least one ring areeach independently hydrogen, halo, (C₁-C₆)alkoxy or (C₁-C₆)alkyl, said(C₁-C₆)alkyl optionally having from one to nine fluorines.

[0176] Compounds of Formula III and their methods of manufacture aredisclosed in commonly assigned U.S. Pat. No. 6,147,089, U.S. Pat. No.6,310,075, and European Patent Application No. 99307240.4 filed Sep. 14,1999, all of which are incorporated herein by reference in theirentireties for all purposes.

[0177] In a preferred embodiment, the CETP inhibitor is selected fromone of the following compounds of Formula III:

[0178] [2R, 4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylicacid ethyl ester;

[0179] [6R, 8S]8-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methyl-3,6,7,8-tetrahydro-1H-2-thia-5-aza-cyclopenta[b]naphthalene-5-carboxylicacid ethyl ester;

[0180] [6R, 8S]8-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methyl-3,6,7,8-tetrahydro-2H-furo[2,3-g]quinoline-5-carboxylicacid ethyl ester;

[0181] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-3,4,6,8-tetrahydro-2H-furo[3,4-g]quinoline-1-carboxylicacid ethyl ester;

[0182] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-3,4,6,7,8,9-hexahydro-2H-benzo[g]quinoline-1-carboxylicacid propyl ester;

[0183]7R,9S]9-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-methyl-1,2,3,7,8,9-hexahydro-6-aza-cyclopenta[a]naphthalene-6-carboxylicacid ethyl ester; and

[0184] [6S,8R]6-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-8-methyl-1,2,3,6,7,8-hexahydro-9-aza-cyclopenta[a]naphthalene-9-carboxylicacid ethyl ester.

[0185] Another class of CETP inhibitors that finds utility with thepresent invention consists of4-carboxyamino-2-substituted-1,2,3,4,-tetrahydroquinolines, having theFormula IV

[0186] and pharmaceutically acceptable salts, enantiomers, orstereoisomers of said compounds;

[0187] wherein R_(IV-1) is hydrogen, Y_(IV), W_(IV)—X_(IV) orW_(IV)—Y_(IV);

[0188] wherein W_(IV) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

[0189] X_(IV) is —O—Y_(IV), —S—Y_(IV), —N(H)—Y_(IV) or —N—(Y_(IV))₂;

[0190] wherein Y_(IV) for each occurrence is independently Z_(IV) or afully saturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(IV);

[0191] wherein Z_(IV) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0192] wherein said Z_(IV) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; R_(IV-2) is a partially saturated, fully saturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one or two heteroatoms selected independently from oxygen,sulfur and nitrogen wherein said carbon atoms are optionally mono-, di-or tri-substituted independently with halo, said carbon is optionallymono-substituted with oxo, said carbon is optionally mono-substitutedwith hydroxy, said sulfur is optionally mono- or di-substituted withoxo, said nitrogen is optionally mono- or di-substituted with oxo; orsaid R_(IV-2) is a partially saturated, fully saturated or fullyunsaturated three to seven membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen,wherein said R_(IV-2) ring is optionally attached through (C₁-C₄)alkyl;

[0193] wherein said R_(IV-2) ring is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, oxo or (C₁-C₆)alkyloxycarbonyl;

[0194] with the proviso that R_(IV-2) is not methyl;

[0195] R_(IV-3) is hydrogen or Q_(IV);

[0196] wherein Q_(IV) is a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(IV);

[0197] wherein V_(IV) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0198] wherein said V_(IV) substituent is optionally mono-, di-, tri-,or tetra-substituted independently with halo, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro,cyano, oxo, carboxamoyl, mono-N- or di-N,N-(C₁-C₆) alkylcarboxamoyl,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionallymono-, di- or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are also optionallysubstituted with from one to nine fluorines;

[0199] R_(IV-4) is Q_(IV-1) or V_(IV-1);

[0200] wherein Q_(IV-1) a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with

[0201] V_(IV-1);

[0202] wherein V_(IV-1) is a partially saturated, fully saturated orfully unsaturated three to six membered ring optionally having one totwo heteroatoms selected independently from oxygen, sulfur and nitrogen;

[0203] wherein said V_(IV-1) substituent is optionally mono-, di-, tri-,or tetra-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isalso optionally substituted with from one to nine fluorines;

[0204] wherein either R_(IV-3) must contain V_(IV) or R_(IV-4) mustcontain V_(IV-1); R_(IV-5), R_(IV-6), R_(IV-7) and R_(IV-8) are eachindependently hydrogen, a bond, nitro or halo wherein said bond issubstituted with T_(IV) or a partially saturated, fully saturated orfully unsaturated (C₁-C₁₂) straight or branched carbon chain whereincarbon, may optionally be replaced with one or two heteroatoms selectedindependently from oxygen, sulfur and nitrogen wherein said carbon atomsare optionally mono-, di- or tri-substituted independently with halo,said carbon is optionally mono-substituted with hydroxy, said carbon isoptionally mono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon is optionally mono-substitutedwith T_(IV);

[0205] wherein T_(IV) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0206] wherein said T_(IV) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; and

[0207] wherein R_(IV-5) and R_(IV-6), or R_(IV-6) and R_(IV-7), and/orR_(IV-7) and R_(IV-8) may also be taken together and can form at leastone four to eight membered ring that is partially saturated or fullyunsaturated optionally having one to three heteroatoms independentlyselected from nitrogen, sulfur and oxygen;

[0208] wherein said ring or rings formed by R_(IV-5) and R_(IV-6), orR_(IV-6) and R_(IV-7), and/or R_(IV-7) and R_(IV-8) are optionallymono-, di- or tri-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; with the proviso that when R_(IV-2) is carboxyl or(C₁-C₄)alkylcarboxyl, then R_(IV-1) is not hydrogen.

[0209] Compounds of Formula IV and their methods of manufacture aredisclosed in commonly assigned U.S. Pat. No. 6,197,786, U.S. applicationSer. No. 09/685,3000 filed Oct. 10, 2000, and PCT Publication No. WO00/17164, all of which are incorporated herein by reference in theirentireties for all purposes.

[0210] In a preferred embodiment, the CETP inhibitor is selected fromone of the following compounds of Formula IV:

[0211] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0212] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-cyclopropyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0213] [2S,4S]2-cyclopropyl-4-[(3,5-dichloro-benzyl)-methoxycarbonyl-amino]-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0214] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester;

[0215] [2R,4R]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinaline-1-carboxylicacid isopropyl ester;

[0216] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0217] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0218] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0219] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0220] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid 2-hydroxy-ethyl ester;

[0221] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0222] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0223] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester; and

[0224] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester.

[0225] Another class of CETP inhibitors that finds utility with thepresent invention consists of 4-aminosubstituted-2-substituted-1,2,3,4,-tetrahydroquinolines, having theFormula V

[0226] and pharmaceutically acceptable salts, enantiomers, orstereoisomers of said compounds;

[0227] wherein R_(V-1) is Y_(V), W_(V)-X_(V) or W_(V)-Y_(V);

[0228] wherein W_(V) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

[0229] X_(V) is —O—Y_(V), —S—Y_(V), —N(H)—Y_(V) or —N—(Y_(V))₂;

[0230] wherein Y_(V) for each occurrence is independently Z_(V) or afully saturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(V);

[0231] wherein Z_(V) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0232] wherein said Z_(V) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines;

[0233] R_(V-2) is a partially saturated, fully saturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one or two heteroatoms selected independently from oxygen,sulfur and nitrogen wherein said carbon atoms are optionally mono-, di-or tri-substituted independently with halo, said carbon is optionallymono-substituted with oxo, said carbon is optionally mono-substitutedwith hydroxy, said sulfur is optionally mono- or di-substituted withoxo, said nitrogen is optionally mono- or di-substituted with oxo; orsaid R_(V-2) is a partially saturated, fully saturated or fullyunsaturated three to seven membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen,wherein said R_(V-2) ring is optionally attached through (C₁-C₄)alkyl;

[0234] wherein said R_(V-2) ring is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, oxo or (C₁-C₆)alkyloxycarbonyl;

[0235] R_(V-3) is hydrogen or Q_(V);

[0236] wherein Q_(V) is a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono-, or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(V);

[0237] wherein V_(V) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0238] wherein said V_(V) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxamoyl, mono-N- or di-N,N-(C₁-C₆) alkylcarboxamoyl, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are also optionallysubstituted with from one to nine fluorines;

[0239] R_(V-4) is cyano, formyl, W_(V-1)Q_(V-1), W_(V-1)V_(V-1),(C₁-C₄)alkyleneV_(V-1) or V_(V-2);

[0240] wherein W_(V-1) is carbonyl, thiocarbonyl, SO or SO₂,

[0241] wherein Q_(V-1) a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons may optionally be replaced with one heteroatomselected from oxygen, sulfur and nitrogen and said carbon is optionallymono-, di- or tri-substituted independently with halo, said carbon isoptionally mono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono-, ordi-substituted with oxo, and said carbon chain is optionallymono-substituted with V_(V-1);

[0242] wherein V_(V-1) is a partially saturated, fully saturated orfully unsaturated three to six membered ring optionally having one totwo heteroatoms selected independently from oxygen, sulfur and nitrogen,or a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0243] wherein said V_(V-1) substituent is optionally mono-, di-, tri-,or tetra-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy, oxo, amino, nitro, cyano,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-substituted with oxo,said (C₁-C₆)alkyl substituent is also optionally substituted with fromone to nine fluorines;

[0244] wherein V_(V-2) is a partially saturated, fully saturated orfully unsaturated five to seven membered ring containing one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen;

[0245] wherein said V_(V-2) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₂)alkyl, (C₁-C₂)alkoxy,hydroxy, or oxo wherein said (C₁-C₂)alkyl optionally has from one tofive fluorines; and

[0246] wherein R_(V-4) does not include oxycarbonyl linked directly tothe C⁴ nitrogen;

[0247] wherein either R_(V-3) must contain V_(V) or R_(V-4) must containV_(V-1);

[0248] R_(V-5), R_(V-6), R_(V-7) and R_(V-8) are independently hydrogen,a bond, nitro or halo wherein said bond is substituted with T_(V) or apartially saturated, fully saturated or fully unsaturated (C₁-C₁₂)straight or branched carbon chain wherein carbon may optionally bereplaced with one or two heteroatoms selected independently from oxygen,sulfur and nitrogen, wherein said carbon atoms are optionally mono-, di-or tri-substituted independently with halo, said carbon is optionallymono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon chain is optionallymono-substituted with T_(V);

[0249] wherein T_(V) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0250] wherein said T_(V) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent also optionally has from one to nine fluorines;

[0251] wherein R_(V-5) and R_(V-6), or R_(V-6) and R_(V-7), and/orR_(V-7) and R_(V-8) may also be taken together and can form at least onering that is a partially saturated or fully unsaturated four to eightmembered ring optionally having one to three heteroatoms independentlyselected from nitrogen, sulfur and oxygen;

[0252] wherein said rings formed by R_(V-5) and R_(V-6), or R_(V-6) andR_(V-7), and/or R_(V-7) and R_(V-8) are optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent also optionally has from one to nine fluorines.

[0253] Compounds of Formula V and their methods of manufacture aredisclosed in commonly assigned U.S. Pat. No. 6,140,343, U.S. patentapplication Ser. No. 09/671,221 filed Sep. 27, 2000, and PCT PublicationNo. WO 00/17165, all of which are incorporated herein by reference intheir entireties for all purposes.

[0254] In a preferred embodiment, the CETP inhibitor is selected fromone of the following compounds of Formula V:

[0255] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0256] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester;

[0257] [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester;

[0258] [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0259] [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0260] [2S,4S]4-[1-(3,5-bis-trifluoromethyl-benzyl)-ureido]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0261] [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0262] [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0263] [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester;

[0264] [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0265] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0266] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0267] [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0268] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0269] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0270] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester; and

[0271] [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

[0272] Another class of CETP inhibitors that finds utility with thepresent invention consists of cycloalkano-pyridines having the FormulaVI

[0273] and pharmaceutically acceptable salts, enantiomers, orstereoisomers of said compounds;

[0274] in which

[0275] A_(VI) denotes an aryl containing 6 to 10 carbon atoms, which isoptionally substituted with up to five identical or differentsubstituents in the form of a halogen, nitro, hydroxyl, trifluoromethyl,trifluoromethoxy or a straight-chain or branched alkyl, acyl,hydroxyalkyl or alkoxy containing up to 7 carbon atoms each, or in theform of a group according to the formula —BNR_(VI-3)R_(VI-4), wherein

[0276] R_(VI-3) and R_(VI-4) are identical or different and denote ahydrogen, phenyl or a straight-chain or branched alkyl containing up to6 carbon atoms,

[0277] D_(VI) denotes an aryl containing 6 to 10 carbon atoms, which isoptionally substituted with a phenyl, nitro, halogen, trifluoromethyl ortrifluoromethoxy, or a radical according to the formulaR_(VI-5)-L_(VI)-,

[0278] or R_(VI-9)-T_(VI)-V_(VI)-X_(VI), wherein

[0279] R_(VI-5), R_(VI-6) and R_(VI-9) denote, independently from oneanother, a cycloalkyl containing 3 to 6 carbon atoms, or an arylcontaining 6 to 10 carbon atom or a 5- to 7-membered, optionallybenzo-condensed, saturated or unsaturated, mono-, bi- or tricyclicheterocycle containing up to 4 heteroatoms from the series of S, Nand/or O, wherein the rings are optionally substituted, in the case ofthe nitrogen-containing rings also via the N function, with up to fiveidentical or different substituents in the form of a halogen,trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, astraight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxyor alkoxycarbonyl containing up to 6 carbon atoms each, an aryl ortrifluoromethyl-substituted aryl containing 6 to 10 carbon atoms each,or an optionally benzo-condensed, aromatic 5- to 7-membered heterocyclecontaining up to 3 heteoatoms from the series of S, N and/or O, and/orin the form of a group according to the formula BOR_(VI-10),—SR_(VI-11), —SO₂R_(VI-12) or BNR_(VI-13)R_(VI-14), wherein

[0280] R_(VI-10), R_(VI-11) and R_(VI-12) denote, independently from oneanother, an aryl containing 6 to 10 carbon atoms, which is in turnsubstituted with up to two identical or different substituents in theform of a phenyl, halogen or a straight-chain or branched alkylcontaining up to 6 carbon atoms,

[0281] R_(VI-13) and R_(VI-14) are identical or different and have themeaning of R_(VI-3) and R_(VI-4) given above, or

[0282] R_(VI-5) and/or R_(VI-6) denote a radical according to theformula

[0283] R_(VI-7) denotes a hydrogen or halogen, and

[0284] R_(VI-8) denotes a hydrogen, halogen, azido, trifluoromethyl,hydroxyl, trifluoromethoxy, a straight-chain or branched alkoxy or alkylcontaining up to 6 carbon atoms each, or a radical according to theformula

—NR_(VI-15)R_(VI-16),

[0285] wherein

[0286] R_(VI-15) and R_(VI-16) are identical or different and have themeaning of R_(VI-3) and R_(VI-4) given above, or

[0287] R_(VI-7) and R_(VI-8) together form a radical according to theformula ═O or ═NR_(VI-17), wherein

[0288] R_(VI-17) denotes a hydrogen or a straight-chain or branchedalkyl, alkoxy or acyl containing up to 6 carbon atoms each,

[0289] L_(VI) denotes a straight-chain or branched alkylene oralkenylene chain containing up to 8 carbon atoms each, which areoptionally substituted with up to two hydroxyl groups,

[0290] T_(VI) and X_(VI) are identical or different and denote astraight-chain or branched alkylene chain containing up to 8 carbonatoms, or

[0291] T_(VI) or X_(VI) denotes a bond,

[0292] V_(VI) denotes an oxygen or sulfur atom or an BNR_(VI-18) group,wherein

[0293] R_(VI-18) denotes a hydrogen or a straight-chain or branchedalkyl containing up to 6 carbon atoms or a phenyl,

[0294] E_(VI) denotes a cycloalkyl containing 3 to 8 carbon atoms, or astraight-chain or branched alkyl containing up to 8 carbon atoms, whichis optionally substituted with a cycloalkyl containing 3 to 8 carbonatoms or a hydroxyl, or a phenyl, which is optionally substituted with ahalogen or trifluoromethyl,

[0295] R_(VI-1) and R_(VI-2) together form a straight-chain or branchedalkylene chain containing up to 7 carbon atoms, which must besubstituted with a carbonyl group and/or a radical according to theformula

[0296] wherein

[0297] a and b are identical or different and denote a number equaling1, 2 or 3,

[0298] R_(VI-19) denotes a hydrogen atom, a cycloalkyl containing 3 to 7carbon atoms, a straight-chain or branched silylalkyl containing up to 8carbon atoms, or a straight-chain or branched alkyl containing up to 8carbon atoms, which is optionally substituted with a hydroxyl, astraight-chain or a branched alkoxy containing up to 6 carbon atoms or aphenyl, which may in turn be substituted with a halogen, nitro,trifluoromethyl, trifluoromethoxy or phenyl or tetrazole-substitutedphenyl, and an alkyl that is optionally substituted with a groupaccording to the formula BOR_(VI-22), wherein

[0299] R_(VI-22) denotes a straight-chain or branched acyl containing upto 4 carbon atoms or benzyl, or

[0300] R_(VI-19) denotes a straight-chain or branched acyl containing upto 20 carbon atoms or benzoyl, which is optionally substituted with ahalogen, trifluoromethyl, nitro or trifluoromethoxy, or a straight-chainor branched fluoroacyl containing up to 8 carbon atoms,

[0301] R_(VI-20) and R_(VI-21) are identical or different and denote ahydrogen, phenyl or a straight-chain or branched alkyl containing up to6 carbon atoms, or

[0302] R_(VI-20) and R_(VI-21) together form a 3- to 6-memberedcarbocyclic ring, and a the carbocyclic rings formed are optionallysubstituted, optionally also geminally, with up to six identical ordifferent substituents in the form of trifluoromethyl, hydroxyl,nitrile, halogen, carboxyl, nitro, azido, cyano, cycloalkyl orcycloalkyloxy containing 3 to 7 carbon atoms each, a straight-chain orbranched alkoxycarbonyl, alkoxy or alkylthio containing up to 6 carbonatoms each, or a straight-chain or branched alkyl containing up to 6carbon atoms, which is in turn substituted with up to two identical ordifferent substituents in the form of a hydroxyl, benzyloxy,trifluoromethyl, benzoyl, a straight-chain or branched alkoxy, oxyacylor carboxyl containing up to 4 carbon atoms each and/or a phenyl, whichmay in turn be substituted with a halogen, trifluoromethyl ortrifluoromethoxy, and/or the carbocyclic rings formed are optionallysubstituted, also geminally, with up to five identical or differentsubstituents in the form of a phenyl, benzoyl, thiophenyl orsulfonylbenzyl, which in turn are optionally substituted with a halogen,trifluoromethyl, trifluoromethoxy or nitro, and/or optionally in theform of a radical according to the formula

[0303] wherein

[0304] c is a number equaling 1, 2, 3 or 4,

[0305] d is a number equaling 0 or 1,

[0306] R_(VI-23) and R_(VI-24) are identical or different and denote ahydrogen, cycloalkyl containing 3 to 6 carbon atoms, a straight-chain orbranched alkyl containing up to 6 carbon atoms, benzyl or phenyl, whichis optionally substituted with up to two identical or differentsubstituents in the form of halogen, trifluoromethyl, cyano, phenyl ornitro, and/or the carbocyclic rings formed are optionally substitutedwith a spiro-linked radical according to the formula

[0307] wherein

[0308] W_(VI) denotes either an oxygen atom or a sulfur atom,

[0309] Y_(VI) and Y═_(VI) together form a 2- to 6-memberedstraight-chain or branched alkylene chain,

[0310] e is a number equaling 1, 2, 3, 4, 5, 6 or 7,

[0311] f is a number equaling 1 or 2,

[0312] R_(VI-25), R_(VI-26), R_(VI-27), R_(VI-28), R_(VI-29), R_(VI-30)and R_(VI-31) are identical or different and denote a hydrogen,trifluoromethyl, phenyl, halogen or a straight-chain or branched alkylor alkoxy containing up to 6 carbon atoms each, or

[0313] R_(VI-25) and R_(VI-26) or R_(VI-27) and R_(VI-28) each togetherdenote a straight-chain or branched alkyl chain containing up to 6carbon atoms or

[0314] R_(VI-25) and R_(VI-26) or R_(VI-27) and R_(VI-28) each togetherform a radical according to the formula

[0315] wherein

[0316] W_(VI) has the meaning given above,

[0317] g is a number equaling 1, 2, 3, 4, 5, 6 or 7,

[0318] R_(VI-32) and R_(VI-33) together form a 3- to 7-memberedheterocycle, which contains an oxygen or sulfur atom or a groupaccording to the formula SO, SO₂ or BNR_(VI-34), wherein

[0319] R_(VI-34) denotes a hydrogen atom, a phenyl, benzyl, or astraight-chain or branched alkyl containing up to 4 carbon atoms, andsalts and N oxides thereof, with the exception of 5(6H)-quinolones,3-benzoyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl.

[0320] Compounds of Formula VI and their methods of manufacture aredisclosed in European Patent Application No. EP 818448 A1, U.S. Pat. No.6,207,671 and U.S. Pat. No. 6,069,148, all of which are incorporatedherein by reference in their entireties for all purposes.

[0321] In a preferred embodiment, the CETP inhibitor is selected fromone of the following compounds of Formula VI:

[0322]2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-3-(4-trifluoromethylbenzoyl)-4,6,7,8-tetrahydro-1H-quinolin-5-one;

[0323]2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-3-(4-trifluoromethylbenzoyl)-7,8-dihydro-6H-quinolin-5-one;

[0324][2-cyclopentyl-4-(4-fluorophenyl)-5-hydroxy-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanone;

[0325][5-(t-butyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanone;

[0326][5-(t-butyidimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanol;

[0327]5-(t-butyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-3-[fluoro-(4-trifluoromethylphenyl)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline;and

[0328]2-cyclopentyl-4-(4-fluorophenyl)-3-[fluoro-(4-trifluoromethylphenyl)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol.

[0329] Another class of CETP inhibitors that finds utility with thepresent invention consists of substituted-pyridines having the FormulaVII

[0330] or a pharmaceutically acceptable salt or tautomer thereof,

[0331] wherein

[0332] R_(VII-2) and R_(VII-6) are independently selected from the groupconsisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinatedaralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that atleast one of R_(VII-2) and R_(VII-6) is fluorinated alkyl,chlorofluorinated alkyl or alkoxyalkyl;

[0333] R_(VII-3) is selected from the group consisting of hydroxy,amido, arylcarbonyl, heteroarylcarbonyl, hydroxymethyl

[0334] —CHO,

[0335] —CO₂R_(VII-7), wherein R_(VII-7) is selected from the groupconsisting of hydrogen, alkyl and cyanoalkyl; and

[0336] wherein R_(VII-15a) is selected from the group consisting ofhydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio,arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy,aryloxy, heteroaryloxy and heterocyclyloxy, and

[0337] R_(VII-16a) is selected from the group consisting of alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl,and heterocyclyl, arylalkoxy, trialkylsilyloxy;

[0338] R_(VII-4) is selected from the group consisting of hydrogen,hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl,cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl,heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl,hetereoarylalkenyl, heterocyclylalkenyl, alkoxy, alkenoxy, alkynoxy,aryloxy, heteroaryloxy, heterocyclyloxy, alkanoyloxy, alkenoyloxy,alkynoyloxy, aryloyloxy, heteroaroyloxy, heterocyclyloyloxy,alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, heterocyclyloxycarbonyl, thio, alkylthio,alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio,cycloalkylthio, cycloalkenylthio, alkylthioalkyl, alkenylthioalkyl,alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl,heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl,alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl,heterocyclythioalkenyl, alkylamino, alkenylamino, alkynylamino,arylamino, heteroarylamino, heterocyclylamino, aryldialkylamino,diarylamino, diheteroarylamino, alkylarylamino, alkylheteroarylamino,arylheteroarylamino, trialkylsilyl, trialkenylsilyl, triarylsilyl,—CO(O)N(R_(VII-8a)R_(VII-8b)), wherein R_(VII-8a) and R_(VII-8b) areindependently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl and heterocyclyl, —SO₂R_(VII-9), whereinR_(VII-9) is selected from the group consisting of hydroxy, alkyl,alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,—OP(O)(OR_(VII-10a)) (OR_(VII-10b)), wherein R_(VII-10a) and R_(VII-10b)are independently selected from the group consisting of hydrogen,hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and—OP(S) (OR_(VII-11a)) (OR_(VII-11b)), wherein R_(VII-11a) a andR_(VII-11b) are independently selected from the group consisting ofalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

[0339] R_(VII-5) is selected from the group consisting of hydrogen,hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl,alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy,alkylcarbonyloxyalkyl, alkenylcarbonyloxyalkyl, alkynylcarbonyloxyalkyl,arylcarbonyloxyalkyl, heteroarylcarbonyloxyalkyl,heterocyclylcarbonyloxyalkyl, cycloalkylalkyl, cycloalkenylalkyl,aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl,cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl,alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl,arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl,alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl,arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl,alkoxyalkyl, alkenoxyalkyl, alkynoxylalkyl, aryloxyalkyl,heteroaryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkenyl,alkenoxyalkenyl, alkynoxyalkenyl, aryloxyalkenyl, heteroaryloxyalkenyl,heterocyclyloxyalkenyl, cyano, hydroxymethyl, —CO₂R_(VII-14), whereinR_(VII-14) is selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl and heterocyclyl;

[0340] wherein R_(VII-15b) is selected from the group consisting ofhydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio,arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy,aryloxy, heteroaryloxy, heterocyclyloxy, aroyloxy, and alkylsulfonyloxy,and

[0341] R_(VII-16b) is selected form the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkoxy, andtrialkylsilyloxy;

[0342] wherein R_(VII-17) and R_(VII-18) are independently selected fromthe group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl and heterocyclyl;

[0343] wherein R_(VII-19) is selected from the group consisting ofalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,—SR_(VII-20), —OR_(VII-21), and BR_(VII-22)CO₂R_(VII-23), wherein

[0344] R_(VII-20) is selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aminoalkyl,aminoalkenyl, aminoalkynyl, aminoaryl, aminoheteroaryl,aminoheterocyclyl, alkylheteroarylamino, arylheteroarylamino,

[0345] R_(VII-21) is selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl,

[0346] R_(VII-22) is selected from the group consisting of alkylene orarylene, and

[0347] R_(VII-23) is selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

[0348] wherein R_(VII-24) is selected from the group consisting ofhydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, aralkyl, aralkenyl, and aralkynyl;

[0349] wherein R_(VII-25) is heterocyclylidenyl;

[0350] wherein R_(VII-26) and R_(VII-27) are independently selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, and heterocyclyl;

[0351] wherein R_(VII-28) and R_(VII-29) are independently selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, and heterocyclyl;

[0352] wherein R_(VII-30) and R_(VII-31) are independently alkoxy,alkenoxy, alkynoxy, aryloxy, heteroaryloxy, and heterocyclyloxy; and

[0353] wherein R_(VII-32) and R_(VII-33) are independently selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, and heterocyclyl;

[0354] wherein R_(VII-36) is selected from the group consisting ofalkyl, alkenyl, aryl, heteroaryl and heterocyclyl;

[0355] wherein R_(VII-37) and R_(VII-38) are independently selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, and heterocyclyl;

[0356] wherein R_(VII-30) is selected from the group consisting ofhydrogen, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy,heterocyclyloxy, alkylthio, alkenylthio, alkynylthio, arylthio,heteroarylthio and heterocyclylthio, and

[0357] R_(VII-40) is selected from the group consisting of haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl,cycloalkyl, cycloalkenyl, heterocyclylalkoxy, heterocyclylalkenoxy,heterocyclylalkynoxy, alkylthio, alkenylthio, alkynylthio, arylthio,heteroarylthio and heterocyclylthio;

—N═R_(VII-41),

[0358] wherein R_(VII-41) is heterocyclylidenyl;

[0359] wherein R_(VII-42) is selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl,and

[0360] R_(VII-43) is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl,haloheteroaryl, and haloheterocyclyl;

[0361] wherein R_(VII-44) is selected from the group consisting ofhydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl andheterocyclyl;

—N═S═O;

—N═C═S;

—N═C═O;

—N₃;

—SR_(VII-45)

[0362] wherein R_(VII-45) is selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl,haloheterocyclyl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl,aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl,cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl,alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl,arylthioalkyl,heteroarylthioalkyl, heterocyclylthioalkyl,alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl,arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl,aminocarbonylalkyl, aminocarbonylalkenyl, aminocarbonylalkynyl,aminocarbonylaryl, aminocarbonylheteroaryl, andaminocarbonylheterocyclyl,

—SR_(VII-46), and —CH₂R_(VII-47),

[0363] wherein R_(VII-46) is selected from the group consisting ofalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and

[0364] R_(VII-47) is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl; and

[0365] wherein R_(VII-48) is selected from the group consisting ofhydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl andheterocyclyl, and

[0366] R_(VII-49) is selected from the group consisting of alkoxy,alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl;

[0367] wherein R_(VII-50) is selected from the group consisting ofhydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy andheterocyclyloxy;

[0368] wherein R_(VII-51) is selected from the group consisting ofalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl;and

[0369] wherein R_(VII-53) is selected from the group consisting ofalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

[0370] provided that when R_(VII-5) is selected from the groupconsisting of heterocyclylalkyl and heterocyclylalkenyl, theheterocyclyl radical of the corresponding heterocyclylalkyl orheterocyclylalkenyl is other than δ-lactone; and

[0371] provided that when R_(VII-4) is aryl, heteroaryl or heterocyclyl,and one of R_(VII-2) and R_(VII-6) is trifluoromethyl, then the other ofR_(VII-2) and R_(VII-6) is difluoromethyl.

[0372] Compounds of Formula VII and their methods of manufacture aredisclosed in PCT Publication No. WO 9941237-A1, which is incorporatedherein by reference in its entirety for all purposes.

[0373] In a preferred embodiment, the CETP inhibitor of Formula VII isdimethyl5,5-dithiobis[2-difluoromethyl-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine-carboxylate].

[0374] Another class of CETP inhibitors that finds utility with thepresent invention consists of substituted biphenyls having the FormulaVIII

[0375] or a pharmaceutically acceptable salt, enantiomers, orstereoisomers thereof,

[0376] in which

[0377] A_(VIII) stands for aryl with 6 to 10 carbon atoms, which isoptionally substituted up to 3 times in an identical manner ordifferently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, orby straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbonatoms each, or by a group of the formula

—NR_(VIII-1)R_(VIII-2), wherein

[0378] R_(VIII-1) and R_(VIII-2) are identical or different and denotehydrogen, phenyl, or straight-chain or branched alkyl with up to 6carbon atoms,

[0379] D_(VIII) stands for straight-chain or branched alkyl with up to 8carbon atoms, which is substituted by hydroxy,

[0380] E_(VIII) and L_(VIII) are either identical or different and standfor straight-chain or branched alkyl with up to 8 carbon atoms, which isoptionally substituted by cycloalkyl with 3 to 8 carbon atoms, or standsfor cycloalkyl with 3 to 8 carbon atoms, or

[0381] E_(VIII) has the above-mentioned meaning and

[0382] L_(VIII) in this case stands for aryl with 6 to 10 carbon atoms,which is optionally substituted up to 3 times in an identical manner ordifferently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, orby straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbonatoms each, or by a group of the formula

—NR_(VIII-3)R_(VIII-4), wherein

[0383] R_(VIII-3) and R_(VIII-4) are identical or different and have themeaning given above for R_(VIII-1) and R_(VIII-2), or

[0384] E_(VIII) stands for straight-chain or branched alkyl with up to 8carbon atoms, or stands for aryl with 6 to 10 carbon atoms, which isoptionally substituted up to 3 times in an identical manner ordifferently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, orby straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbonatoms each, or by a group of the formula

—NR_(VIII-5)R_(VIII-6), wherein

[0385] R_(VIII-5) and R_(VIII-6) are identical or different and have themeaning given above for R_(VIII-1) and R_(VIII-2), and

[0386] L_(VIII) in this case stands for straight-chain or branchedalkoxy with up to 8 carbon atoms or for cycloalkyloxy with 3 to 8 carbonatoms, T_(VII) stands for a radical of the formula

[0387] R_(VIII-7)-X_(VIII)- or

[0388] wherein

[0389] R_(VIII-7) and R_(VIII-8) are identical or different and denotecycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbon atoms,or denote a 5- to 7-member aromatic, optionally benzo-condensed,heterocyclic compound with up to 3 heteroatoms from the series S, Nand/or O, which are optionally substituted up to 3 times in an identicalmanner or differently by trifluoromethyl, trifluoromethoxy, halogen,hydroxy, carboxyl, by straight-chain or branched alkyl, acyl, alkoxy, oralkoxycarbonyl with up to 6 carbon atoms each, or by phenyl, phenoxy, orthiophenyl, which can in turn be substituted by halogen,trifluoromethyl, or trifluoromethoxy, and/or the rings are substitutedby a group of the formula

—NR_(VIII-11)R_(VIII-12), wherein

[0390] R_(VIII-11) and R_(VIII-12) are identical or different and havethe meaning given above for R_(VIII-1) and R_(VIII-2) ,

[0391] X_(VIII) denotes a straight or branched alkyl chain or alkenylchain with 2 to 10 carbon atoms each, which are optionally substitutedup to 2 times by hydroxy,

[0392] R_(VIII-9) denotes hydrogen, and

[0393] R_(VIII-10) denotes hydrogen, halogen, azido, trifluoromethyl,hydroxy, mercapto, trifluoromethoxy, straight-chain or branched alkoxywith up to 5 carbon atoms, or a radical of the formula

—NR_(VIII-13)R_(VIII-14), wherein

[0394] R_(VIII-13) and R_(VIII-14) are identical or different and havethe meaning given above for R_(VIII-1) and R_(VIII-2), or

[0395] R_(VIII-9) and R_(VIII-10) form a carbonyl group together withthe carbon atom.

[0396] Compounds of Formula VIII are disclosed in PCT Publication No. WO9804528, which is incorporated herein by reference in its entirety forall purposes.

[0397] Another class of CETP inhibitors that finds utility with thepresent invention consists of substituted 1,2,4-triazoles having theFormula IX

[0398] or a pharmaceutically acceptable salt or tautomer thereof;

[0399] wherein R_(IX-1) is selected from higher alkyl, higher alkenyl,higher alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl,alkylthioalkyl, arylthioalkyl, and cycloalkylalkyl;

[0400] wherein R_(IX-2) is selected from aryl, heteroaryl, cycloalkyl,and cycloalkenyl, wherein

[0401] R_(IX-2) is optionally substituted at a substitutable positionwith one or more radicals independently selected from alkyl, haloalkyl,alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxy, halo, aryloxy,aralkyloxy, aryl, aralkyl, aminosulfonyl, amino, monoalkylamino anddialkylamino; and

[0402] wherein R_(IX-3) is selected from hydrido, —SH and halo;

[0403] provided R_(IX-2) cannot be phenyl or 4-methylphenyl whenR_(IX-1) is higher alkyl and when R_(IX-3) is BSH.

[0404] Compounds of Formula IX and their methods of manufacture aredisclosed in PCT Publication No. WO 9914204, which is incorporatedherein by reference in its entirety for all purposes.

[0405] In a preferred embodiment, the CETP inhibitor is selected fromthe following compounds of Formula IX:

[0406]2,4-dihydro-4-(3-methoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0407]2,4-dihydro-4-(2-fluorophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0408]2,4-dihydro-4-(2-methylphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0409]2,4-dihydro-4-(3-chlorophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0410]2,4-dihydro-4-(2-methoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0411]2,4-dihydro-4-(3-methylphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0412] 4-cyclohexyl-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0413] 2,4-dihydro-4-(3-pyridyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0414]2,4-dihydro-4-(2-ethoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0415]2,4-dihydro-4-(2,6-dimethylphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0416]2,4-dihydro-4-(4-phenoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0417]4-(1,3-benzodioxol-5-yl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0418]4-(2-chlorophenyl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0419]2,4-dihydro-4-(4-methoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0420]2,4-dihydro-5-tridecyl-4-(3-trifluoromethylphenyl)-3H-1,2,4-triazole-3-thione;

[0421] 2,4-dihydro-5-tridecyl-4-(3-fluorophenyl)-3H-1,2,4-triazole-3-thione;

[0422]4-(3-chloro-4-methylphenyl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0423]2,4-dihydro-4-(2-methylthiophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0424]4-(4-benzyloxyphenyl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0425] 2,4-dihydro-4-(2-naphthyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0426]2,4-dihydro-5-tridecyl-4-(4-trifluoromethylphenyl)-3H-1,2,4-triazole-3-thione;

[0427] 2,4-dihydro-4-(1-naphthyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0428]2,4-dihydro-4-(3-methylthiophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0429]2,4-dihydro-4-(4-methylthiophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0430]2,4-dihydro-4-(3,4-dimethoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0431]2,4-dihydro-4-(2,5-dimethoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0432]2,4-dihydro-4-(2-methoxy-5-chlorophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0433]4-(4-aminosulfonylphenyl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0434]2,4-dihydro-5-dodecyl-4-(3-methoxyphenyl)-3H-1,2,4-triazole-3-thione;

[0435]2,4-dihydro-4-(3-methoxyphenyl)-5-tetradecyl-3H-1,2,4-triazole-3-thione;

[0436]2,4-dihydro-4-(3-methoxyphenyl)-5-undecyl-3H-1,2,4-triazole-3-thione;and

[0437]2,4-dihydro-(4-methoxyphenyl)-5-pentadecyl-3H-1,2,4-triazole-3-thione.

[0438] Another class of CETP inhibitors that finds utility with thepresent invention consists of hetero-tetrahydroquinolines having theFormula X

[0439] and pharmaceutically acceptable salts, enantiomers, orstereoisomers or N-oxides of said compounds;

[0440] in which

[0441] A_(X) represents cycloalkyl with 3 to 8 carbon atoms or a 5 to7-membered, saturated, partially saturated or unsaturated, optionallybenzo-condensed heterocyclic ring containing up to 3 heteroatoms fromthe series comprising S, N and/or O, that in case of a saturatedheterocyclic ring is bonded to a nitrogen function, optionally bridgedover it, and in which the aromatic systems mentioned above areoptionally substituted up to 5-times in an identical or differentsubstituents in the form of halogen, nitro, hydroxy, trifluoromethyl,trifluoromethoxy or by a straight-chain or branched alkyl, acyl,hydroxyalkyl or alkoxy each having up to 7 carbon atoms or by a group ofthe formula BNR_(X-3)R_(X-4),

[0442] in which

[0443] R_(X-3) and R_(X-4) are identical or different and denotehydrogen, phenyl or straight-chain or branched alkyl having up to 6carbon atoms,

[0444] or

[0445] A_(X) represents a radical of the formula

[0446] D_(X) represents an aryl having 6 to 10 carbon atoms, that isoptionally substituted by phenyl, nitro, halogen, trifluormethyl ortrifluormethoxy, or it represents a radical of the formula

[0447] or

R_(X-9)—T_(X)—V_(X)—X_(X)

[0448] in which

[0449] R_(X-5), R_(X-6) and R_(X-9) independently of one another denotecycloalkyl having 3 to 6 carbon atoms, or an aryl having 6 to 10 carbonatoms or a 5- to 7-membered aromatic, optionally benzo-condensedsaturated or unsaturated, mono-, bi-, or tricyclic heterocyclic ringfrom the series consisting of S, N and/or O, in which the rings aresubstituted, optionally, in case of the nitrogen containing aromaticrings via the N function, with up to 5 identical or differentsubstituents in the form of halogen, trifluoromethyl, nitro, hydroxy,cyano, carbonyl, trifluoromethoxy, straight straight-chain or branchedacyl, alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl eachhaving up to 6 carbon atoms, by aryl or trifluoromethyl-substituted aryleach having 6 to 10 carbon atoms or by an, optionally benzo-condensed,aromatic 5- to 7-membered heterocyclic ring having up to 3 heteroatomsfrom the series consisting of S, N, and/or O, and/or substituted by agroup of the formula BOR_(X-10), —SR_(X-11), SO₂R_(X-12) orBNR_(X-13)R_(X-14),

[0450] in which

[0451] R_(X-10), R_(X-11) and R_(X-12) independently from each otherdenote aryl having 6 to 10 carbon atoms, which is in turn substitutedwith up to 2 identical or different substituents in the form of phenyl,halogen or a straight-chain or branched alkyl having up to 6 carbonatoms,

[0452] R_(X-13) and R_(X-14) are identical or different and have themeaning of R_(X-3) and R_(X-4) indicated above,

[0453] or

[0454] R_(X-5) and/or R_(X-6) denote a radical of the formula

[0455] R_(X-7) denotes hydrogen or halogen, and

[0456] R_(X-8) denotes hydrogen, halogen, azido, trifluoromethyl,hydroxy, trifluoromethoxy, straight-chain or branched alkoxy or alkylhaving up to 6 carbon atoms or a radical of the formula

BNR_(X-15)R_(X-16),

[0457] in which

[0458] R_(X-15) and R_(X-16) are identical or different and have themeaning of R_(X-3) and R_(X-4) indicated above,

[0459] or

[0460] R_(X-7) and R_(X-8) together form a radical of the formula ═O or═NR_(X-17),

[0461] in which

[0462] R_(X-17) denotes hydrogen or straight chain or branched alkyl,alkoxy or acyl having up to 6 carbon atoms,

[0463] L_(X) denotes a straight chain or branched alkylene or alkenylenechain having up to 8 carbon atoms, that are optionally substituted withup to 2 hydroxy groups,

[0464] T_(X) and X_(X) are identical or different and denote a straightchain or branched alkylene chain with up to 8 carbon atoms

[0465] or

[0466] T_(X) or X_(X) denotes a bond,

[0467] V_(X) represents an oxygen or sulfur atom or an BNR_(X-18)-group,in which

[0468] R_(X-18) denotes hydrogen or straight chain or branched alkylwith up to 6 carbon atoms or phenyl,

[0469] E_(X) represents cycloalkyl with 3 to 8 carbon atoms, or straightchain or branched alkyl with up to 8 carbon atoms, that is optionallysubstituted by cycloalkyl with 3 to 8 carbon atoms or hydroxy, orrepresents a phenyl, that is optionally substituted by halogen ortrifluoromethyl,

[0470] R_(X-1) and R_(X-2) together form a straight-chain or branchedalkylene chain with up to 7 carbon atoms, that must be substituted bycarbonyl group and/or by a radical with the formula

[0471] in which a and b are identical or different and denote a numberequaling 1,2, or 3,

[0472] R_(X-19) denotes hydrogen, cycloalkyl with 3 up to 7 carbonatoms, straight chain or branched silylalkyl with up to 8 carbon atomsor straight chain or branched alkyl with up to 8 carbon atoms, that areoptionally substituted by hydroxyl, straight chain or branched alkoxywith up to 6 carbon atoms or by phenyl, which in turn might besubstituted by halogen, nitro, trifluormethyl, trifluoromethoxy or byphenyl or by tetrazole-substituted phenyl, and alkyl, optionally besubstituted by a group with the formula BOR_(X-22),

[0473] in which

[0474] R_(X-22) denotes a straight chain or branched acyl with up to 4carbon atoms or benzyl,

[0475] or

[0476] R_(X-19) denotes straight chain or branched acyl with up to 20carbon atoms or benzoyl, that is optionally substituted by halogen,trifluoromethyl, nitro or trifluoromethoxy, or it denotes straight chainor branched fluoroacyl with up to 8 carbon atoms and 9 fluorine atoms,

[0477] R_(X-20) and R_(X-21) are identical or different and denotehydrogen, phenyl or straight chain or branched alkyl with up to 6 carbonatoms,

[0478] or

[0479] R_(X-20) and R_(X-21) together form a 3- to 6- memberedcarbocyclic ring, and the carbocyclic rings formed are optionallysubstituted, optionally also geminally, with up to six identical ordifferent substituents in the form of triflouromethyl, hydroxy, nitrile,halogen, carboxyl, nitro, azido, cyano, cycloalkyl or cycloalkyloxy with3 to 7 carbon atoms each, by straight chain or branched alkoxycarbonyl,alkoxy or alkylthio with up to 6 carbon atoms each or by straight chainor branched alkyl with up to 6 carbon atoms, which in turn issubstituted with up to 2 identically or differently by hydroxyl,benzyloxy, trifluoromethyl, benzoyl, straight chain or branched alkoxy,oxyacyl or carbonyl with up to 4 carbon atoms each and/or phenyl, whichmay in turn be substituted with a halogen, trifuoromethyl ortrifluoromethoxy, and/or the formed carbocyclic rings are optionallysubstituted, also geminally, with up to 5 identical or differentsubstituents in the form of phenyl, benzoyl, thiophenyl orsulfonylbenzyl, which in turn are optionally substituted by halogen,trifluoromethyl, trifluoromethoxy or nitro, and/or optionally aresubstituted by a radical with the formula

—SO₂—C₆H₅, —(CO)_(d)NR_(X-23)R_(X-24) or ═O,

[0480] in which

[0481] c denotes a number equaling 1, 2, 3, or 4,

[0482] d denotes a number equaling 0 or 1,

[0483] R_(X-23) and R_(X-24) are identical or different and denotehydrogen, cycloalkyl with 3 to 6 carbon atoms, straight chain orbranched alkyl with up to 6 carbon atoms, benzyl or phenyl, that isoptionally substituted with up to 2 identically or differently byhalogen, trifluoromethyl, cyano, phenyl or nitro, and/or the formedcarbocyclic rings are substituted optionally by a spiro-linked radicalwith the formula

[0484] in which

[0485] W_(X) denotes either an oxygen or a sulfur atom

[0486] Y_(X) and Y′_(X) together form a 2 to 6 membered straight chainor branched alkylene chain,

[0487] e denotes a number equaling 1, 2, 3, 4, 5, 6, or 7,

[0488] f denotes a number equaling 1 or 2,

[0489] R_(X-25), R_(X-26), R_(X-27), R_(X-28), R_(X-29), R_(X-30) andR_(X-31) are identical or different and denote hydrogen,trifluoromethyl, phenyl, halogen or straight chain or branched alkyl oralkoxy with up to 6 carbon atoms each,

[0490] or

[0491] R_(X-25) and R_(X-26) or R_(X-27) and R_(X-28) respectively formtogether a straight chain or branched alkyl chain with up to 6 carbonatoms,

[0492] or

[0493] R_(X-25) and R_(X-26) or R_(X-27) and R_(X-28) each together forma radical with the formula

[0494] in which

[0495] W_(X) has the meaning given above,

[0496] g denotes a number equaling 1, 2, 3, 4, 5, 6, or 7,

[0497] R_(X-32) and R_(X-33) form together a 3- to 7- memberedheterocycle, which contains an oxygen or sulfur atom or a group with theformula SO, SO₂ or —NR_(X-34),

[0498] in which

[0499] R_(X-34) denotes hydrogen, phenyl, benzyl or straight or branchedalkyl with up to 4 carbon atoms.

[0500] Compounds of Formula X and their methods of manufacture aredisclosed in PCT Publication No. WO 9914215, which is incorporatedherein by reference in its entirety for all purposes.

[0501] In a preferred embodiment, the CETP inhibitor is selected fromthe following compounds of Formula X:

[0502]2-cyclopentyl-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-3-(4-trifluoromethylbenxoyl)-5,6,7,8-tetrahydroquinoline;

[0503]2-cyclopentyl-3-[fluoro-(4-trifluoromethylphenyl)methyl]-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-5,6,7,8-tetrahydroquinoline;and

[0504]2-cyclopentyl-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-3-(trifluoromethylbenxyl)-5,6,7,8-tetrahydroquinoline.

[0505] Another class of CETP inhibitors that finds utility with thepresent invention consists of substituted tetrahydro naphthalines andanalogous compound having the Formula XI

[0506] and stereoisomers, stereoisomer mixtures, and salts thereof, inwhich

[0507] A_(XI) stands for cycloalkyl with 3 to 8 carbon atoms, or standsfor aryl with 6 to 10 carbon atoms, or stands for a 5- to 7-membered,saturated, partially unsaturated or unsaturated, possiblybenzocondensated, heterocycle with up to 4 heteroatoms from the seriesS, N and/or O, where aryl and the heterocyclic ring systems mentionedabove are substituted up to 5-fold, identical or different, by cyano,halogen, nitro, carboxyl, hydroxy, trifluoromethyl, trifluoro- methoxy,or by straight-chain or branched alkyl, acyl, hydroxyalkyl, alkylthio,alkoxycarbonyl, oxyalkoxycarbonyl or alkoxy each with up to 7 carbonatoms, or by a group of the formula

—NR_(XI-3)R_(X-4),

[0508] in which

[0509] R_(XI-3) and R_(XI-4) are identical or different and denotehydrogen, phenyl, or straight-chain or branched alkyl with up to 6carbon atoms

[0510] D_(XI) stands for a radical of the formula

[0511] in which

[0512] R_(XI-5), R_(XI-6) and R_(XI-9), independent of each other,denote cycloalkyl with 3 to 6 carbon atoms, or denote aryl with 6 to 10carbon atoms, or denote a 5- to 7-membered, possibly benzocondensated,saturated or unsaturated, mono-, bi- or tricyclic heterocycle with up to4 heteroatoms of the series S, N and/or O, where the cycles are possiblysubstitutedCin the case of the nitrogen-containing rings also via theN-functionCup to 5-fold, identical or different, by halogen,trifluoromethyl, nitro, hydroxy, cyano, carboxyl, trifluoromethoxy,straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxyor alkoxycarbonyl with up to 6 carbon atoms each. by aryl ortrifluoromethyl substituted aryl with 6 to 10 carbon atoms each, or by apossibly benzocondensated aromatic 5- to 7-membered heterocycle with upto 3 heteroatoms of the series S, N and/or O, and/or are substituted bya group of the formula

—OR_(XI-10), —SR_(XI-11), —SO₂R_(XI-12) or —NR_(XI-13)R_(XI-14),

[0513] in which

[0514] R_(XI-10), R_(XI-11) and R_(XI-12), independent of each other,denote aryl with 6 to 10 carbon atoms, which itself is substituted up to2-fold, identical or different, by phenyl, halogen. or by straight-chainor branched alkyl with up to 6 carbon atoms,

[0515] R_(XI-13) and R_(XI-14) are identical or different and have themeaning given above for R_(XI-3) and R_(XI-4),

[0516] or

[0517] R_(XI-5) and/or R_(XI-6) denote a radical of the formula

[0518] R_(XI-7) denotes hydrogen, halogen or methyl,

[0519] and

[0520] R_(XI-8) denotes hydrogen, halogen, azido, trifluoromethyl,hydroxy, trifluoromethoxy, straight-chain or branched alkoxy or alkylwith up to 6 carbon atoms each, or a radical of the formula—NR_(XI-15)R_(XI-16),

[0521] in which

[0522] R_(XI-15) and R_(XI-16) are identical or different and have themeaning given above for R_(XI-3) and R_(XI-4),

[0523] or

[0524] R_(XI-7) and R_(XI-8) together form a radical of the formula ═Oor ═NR_(XI-17), in which

[0525] R_(XI-17) denotes hydrogen or straight-chain or branched alkyl,alkoxy or acyl with up to 6 carbon atoms each,

[0526] L_(XI) denotes a straight-chain or branched alkylene- oralkenylene chain with up to 8 carbon atoms each, which is possiblysubstituted up to 2-fold by hydroxy,

[0527] T_(XI) and X_(XI) are identical or different and denote astraight-chain or branched alkylene chain with up to 8 carbon atoms,

[0528] or

[0529] T_(XI) and X_(XI) denotes a bond,

[0530] V_(XI) stands for an oxygen- or sulfur atom or for an —NR_(XI-18)group,

[0531] in which

[0532] R_(XI-18) denotes hydrogen or straight-chain or branched alkylwith up to 6 carbon atoms, or phenyl,

[0533] E_(XI) stands for cycloalkyl with 3 to 8 carbon atoms, or standsfor straight-chain or branched alkyl with up to 8 carbon atoms, which ispossibly substituted by cycloalkyl with 3 to 8 carbon atoms or hydroxy,or stands for phenyl, which is possibly substituted by halogen ortrifluoromethyl,

[0534] R_(XI-1) and R_(XI-2) together form a straight-chain or branchedalkylene chain with up to 7 carbon atoms, which must be substituted by acarbonyl group and/or by a radical of the formula

[0535] in which

[0536] a and b are identical or different and denote a number 1, 2 or 3

[0537] R_(XI-19) denotes hydrogen, cycloalkyl with 3 to 7 carbon atoms,straight-chain or branched silylalkyl with up to 8 carbon atoms, orstraight-chain or branched alkyl with up to 8 carbon atoms, which ispossibly substituted by hydroxy, straight-chain or branched alkoxy withup to 6 carbon atoms, or by phenyl, which itself can be substituted byhalogen, nitro, trifluoromethyl, trifluoromethoxy or by phenylsubstituted by phenyl or tetrazol, and alkyl is possibly substituted bya group of the formula —OR_(XI-22),

[0538] in which

[0539] R_(XI-22) denotes straight-chain or branched acyl with up to 4carbon atoms, or benzyl,

[0540] or

[0541] R_(XI-19) denotes straight-chain or branched acyl with up to 20carbon atoms or benzoyl, which is possibly substituted by halogen,trifluoromethyl, nitro or trifluoromethoxy, or denotes straight-chain orbranched fluoroacyl with up to 8 carbon atoms and 9 fluorine atoms,

[0542] R_(XI-20) and R_(XI-21) are identical or different, denotinghydrogen, phenyl or straight-chain or branched alkyl with up to 6 carbonatoms,

[0543] or

[0544] R_(XI-20) and R_(XI-21) together form a 3- to 6-memberedcarbocycle, and, possibly also geminally, the alkylene chain formed byR_(XI-1) and R_(XI-2), is possibly substituted up to 6-fold, identicalor different, by trifluoromethyl, hydroxy, nitrile, halogen, carboxyl,nitro, azido, cyano, cycloalkyl or cycloalkyloxy with 3 to 7 carbonatoms each, by straight-chain or branched alkoxycarbonyl, alkoxy oralkoxythio with up to 6 carbon atoms each, or by straight- chain orbranched alkyl with up to 6 carbon atoms, which itself is substituted upto 2-fold, identical or different. by hydroxyl, benzyloxy,trifluoromethyl, benzoyl, straight-chain or branched alkoxy, oxyacyl orcarboxyl with up to 4 carbon atoms each, and/or phenyl- which itself canbe substituted by halogen, trifluoromethyl or trifluoromethoxy, and/orthe alkylene chain formed by R_(XI-1) and R_(XI-2) is substituted, alsogeminally, possibly up to 5-fold, identical or different, by phenyl,benzoyl, thiophenyl or sulfobenzyl -which themselves are possiblysubstituted by halogen, trifluoromethyl, trifluoromethoxy or nitro,and/or the alkylene chain formed by R_(XI-1) and R_(XI-2) is possiblysubstituted by a radical of the formula

—SO₂—C₆H₅, —(CO)_(d)NR_(XI-23)R_(XI-24) or ═O,

[0545] in which

[0546] c denotes a number 1, 2, 3 or 4,

[0547] d denotes a number 0 or 1,

[0548] R_(XI-23) and R_(XI-24) are identical or different and denotehydrogen, cycloalkyl with 3 to 6 carbon atoms, straight-chain orbranched alkyl with up to 6 carbon atoms, benzyl or phenyl, which ispossibly substituted up to 2-fold. identical or different, by halogen,trifluoromethyl, cyano, phenyl or nitro, and/or the alkylene chainformed by R_(XI-1) and R_(XI-2) is possibly substituted by aspiro-jointed radical of the formula

[0549] in which

[0550] W_(XI) denotes either an oxygen or a sulfur atom,

[0551] Y_(XI) and Y′_(XI) together form a 2- to 6-memberedstraight-chain or branched alkylene chain,

[0552] e is a number 1, 2, 3, 4, 5, 6 or 7,

[0553] f denotes a number 1 or 2,

[0554] R_(XI-25), R_(XI-26), R_(XI-27), R_(XI-28), R_(XI-29), R_(XI-30)and R_(XI-31) are identical or different and denote hydrogen,trifluoromethyl, phenyl, halogen, or straight-chain or branched alkyl oralkoxy with up to 6 carbon atoms each,

[0555] or

[0556] R_(XI-25) and R_(XI-26) or R_(XI-27) and R_(XI-28) together forma straight-chain or branched alkyl chain with up to 6 carbon atoms,

[0557] or

[0558] R_(XI-25) and R_(XI-26) or R_(XI-27) and R_(XI-28) together forma radical of the formula

[0559] in which

[0560] W_(XI) has the meaning given above,

[0561] g is a number 1, 2, 3, 4, 5, 6 or 7,

[0562] R_(XI-32) and R_(XI-33) together form a 3- to 7-memberedheterocycle that contains an oxygen- or sulfur atom or a group of theformula SO, SO₂ or —NR_(XI-34),

[0563] in which

[0564] R_(XI-34) denotes hydrogen, phenyl, benzyl, or straight-chain orbranched alkyl with up to 4 carbon atoms.

[0565] Compounds of Formula XI and their methods of manufacture aredisclosed in PCT Publication No. WO 9914174, which is incorporatedherein by reference in its entirety for all purposes.

[0566] Another class of CETP inhibitors that finds utility with thepresent invention consists of 2-aryl-substituted pyridines having theFormula (XII)

[0567] or pharmaceutically acceptable salts, enantiomers, orstereoisomers of said compounds,

[0568] in which

[0569] A_(XII) and E_(XII) are identical or different and stand for arylwith 6 to 10 carbon atoms which is possibly substituted, up to 5-foldidentical or different, by halogen, hydroxy, trifluoromethyl,trifluoromethoxy, nitro or by straight-chain or branched alkyl, acyl,hydroxy alkyl or alkoxy with up to 7 carbon atoms each, or by a group ofthe formula —NR_(XII-1)R_(XII-2),

[0570] where

[0571] R_(XII-1) and R_(XII-2) are identical or different and are meantto be hydrogen, phenyl or straight-chain or branched alkyl with up to 6carbon atoms,

[0572] D_(XII) stands for straight-chain or branched alkyl with up to 8carbon atoms, which is substituted by hydroxy,

[0573] L_(XII) stands for cycloalkyl with 3 to 8 carbon atoms or forstraight-chain or branched alkyl with up to 8 carbon atoms, which ispossibly substituted by cycloalkyl with 3 to 8 carbon atoms, or byhydroxy,

[0574] T_(XII) stands for a radical of the formula R_(XII-3)-X_(XII) or

[0575] where

[0576] R_(XII-3) and R_(XII-4) are identical or different and are meantto be cycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbonatoms, or a 5- to 7-membered aromatic, possibly benzocondensatedheterocycle with up to 3 heteroatoms from the series S, N and/or O,which are possibly substituted up to 3-fold identical or different, bytrifluoromethyl, trifluoromethoxy, halogen, hydroxy, carboxyl, nitro, bystraight-chain or branched alkyl, acyl, alkoxy or alkoxycarbonyl with upto 6 carbon atoms each or by phenyl, phenoxy or phenylthio which in turncan be substituted by halogen. trifluoromethyl or trifluoromethoxy,and/or where the cycles are possibly substituted by a group of theformula —NR_(XII-7)R_(XII-8),

[0577] where

[0578] R_(XII-7) and R_(XII-8) are identical or different and have themeaning of R_(XII-1) and R_(XII-2) given above,

[0579] X_(XII) is a straight-chain or branched alkyl or alkenyl with 2to 10 carbon atoms each, possibly substituted up to 2-fold by hydroxy orhalogen,

[0580] R_(XII-5) stands for hydrogen,

[0581] and

[0582] R_(XII-6) means to be hydrogen, halogen, mercapto, azido,trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branchedalkoxy with up to 5 carbon atoms, or a radical of the formulaBNR_(XII-9)R_(XII-10),

[0583] where

[0584] R_(XII-9) and R_(XII-10) are identical or different and have themeaning of R_(XII-1) and R_(XII-2) given above,

[0585] or

[0586] R_(XII-5) and R_(XII-6), together with the carbon atom, form acarbonyl group.

[0587] Compounds of Formula XII and their methods of manufacture aredisclosed in EP 796846-A1, U.S. Pat. No. 6,127,383 and U.S. Pat. No.5,925,645, all of which are incorporated herein by reference in theirentireties for all purposes.

[0588] In a preferred embodiment, the CETP inhibitor is selected fromthe following compounds of Formula XII:

[0589]4,6-bis-(p-fluorophenyl)-2-isopropyl-3-[(p-trifluoromethylphenyl)-(fluoro)-methyl]-5-(1-hydroxyethyl)pyridine;

[0590]2,4-bis-(4-fluorophenyl)-6-isopropyl-5-[4-(trifluoromethylphenyl)-fluoromethyl]-3-hydroxymethyl)pyridine;and

[0591]2,4-bis-(4-fluorophenyl)-6-isopropyl-5-[2-(3-trifluoromethylphenyl)vinyl]-3-hydroxymethyl)pyridine.

[0592] Another class of CETP inhibitors that finds utility with thepresent invention consists of compounds having the Formula (XIII)

[0593] or pharmaceutically acceptable salts, enantiomers, stereoisomers,hydrates, or solvates of said compounds, in which

[0594] R_(XIII) is a straight chain or branched C₁₋₁₀ alkyl; straightchain or branched C₂₋₁₀ alkenyl; halogenated C₁₋₄ lower alkyl; C₃₋₁₀cycloalkyl that may be substituted; C₅₋₈ cycloalkenyl that may besubstituted; C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl that may be substituted; arylthat may be substituted; aralkyl that may be substituted; or a 5- or6-membered heterocyclic group having 1 to 3 nitrogen atoms, oxygen atomsor sulfur atoms that may be substituted,

[0595] X_(XIII-1), X_(XIII-2), X_(XIII-3), X_(XIII-4) may be the same ordifferent and are a hydrogen atom; halogen atom; C₁₋₄ lower alkyl;halogenated C₁₋₄ lower alkyl; C₁₋₄ lower alkoxy; cyano group; nitrogroup; acyl; or aryl, respectively;

[0596] Y_(XIII) is —CO—; or BSO₂—; and

[0597] Z_(XIII) is a hydrogen atom; or mercapto protective group.

[0598] Compounds of Formula XIII and their methods of manufacture aredisclosed in PCT Publication No. WO 98/35937, which is incorporatedherein by reference in its entirety for all purposes.

[0599] In a preferred embodiment, the CETP inhibitor is selected fromthe following compounds of Formula XIII:

[0600] N,N′-(dithiodi-2,1-phenylene)bis[2,2-dimethyl-propanamide];

[0601]N,N′-(dithiodi-2,1-phenylene)bis[1-methyl-cyclohexanecarboxamide];

[0602]N,N′-(dithiodi-2,1-phenylene)bis[1-(3-methylbutyl)-cyclopentanecarboxamide];

[0603]N,N′-(dithiodi-2,1-phenylene)bis[1-(3-methylbutyl)-cyclohexanecarboxamide];

[0604] N,N′-(dithiodi-2,1-phenylene)bis[l-(2-ethylbutyl)-cyclohexanecarboxamide];

[0605]N,N′-(dithiodi-2,1-phenylene)bis-tricyclo[3.3.1.1^(3,7)]decane-1-carboxamide;

[0606] propanethioic acid,2-methyl-,S-[2[[[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino]phenyl]ester;

[0607] propanethioic acid, 2,2-dimethyl-,S-[2-[[[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino]phenyl] ester; and

[0608] ethanethioic acid,S-[2-[[[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino]phenyl] ester.

[0609] Another class of CETP inhibitors that finds utility with thepresent invention consists of polycyclic aryl and heteroaryltertiary-heteroalkylamines having the Formula XIV

[0610] and pharmaceutically acceptable forms thereof, wherein:

[0611] n_(XIV) is an integer selected from 0 through 5;

[0612] R_(XIV-1) is selected from the group consisting of haloalkyl,haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;

[0613] X_(XIV) is selected from the group consisting of O, H, F, S,S(O),NH, N(OH), N(alkyl), and N(alkoxy);

[0614] R_(XIV-16) is selected from the group consisting of hydrido,alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl,alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl,heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl,halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl,perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, monocarboalkoxyalkyl,monocarboalkoxy, dicarboalkoxyalkyl, monocarboxamido, monocyanoalkyl,dicyanoalkyl, carboalkoxycyanoalkyl, acyl, aroyl, heteroaroyl,heteroaryloxyalkyl, dialkoxyphosphonoalkyl, trialkylsilyl, and a spacerselected from the group consisting of a covalent single bond and alinear spacer moiety having from 1 through 4 contiguous atoms linked tothe point of bonding of an aromatic substituent selected from the groupconsisting of R_(XIV-4), R_(XIV-8), R_(XIV-9), and R_(XIV-13) to form aheterocyclyl ring having from 5 through 10 contiguous members with theprovisos that said spacer moiety is other than a covalent single bondwhen R_(XIV-2) is alkyl and there is no R_(XIV-16) wherein X is H or F;

[0615] D_(XIV-1), D_(XIV-2), J_(XIV-1), J_(XIV-2) and K_(XIV-1) areindependently selected from the group consisting of C, N, O, S and acovalent bond with the provisos that no more than one of D_(XIV-1),D_(XIV-2), J_(XIV-1), J_(XIV-2) and K_(XIV-1) is a covalent bond, nomore than one of D_(XIV-1), D_(XIV-2), J_(XIV-1), J_(XIV-2) andK_(XIV-1) is O, no more than one of D_(XIV-1), D_(XIV-2), J_(XIV-1),J_(XIV-2) and K_(XIV-1) is S, one of D_(XIV-1), D_(XIV-2), J_(XIV-1),J_(XIV-2) and K_(XIV-1) must be a covalent bond when two of D_(XIV-1),D_(XIV-2), J_(XIV-1), J_(XIV-2) and K_(XIV-1) are O and S, and no morethan four of D_(XIV-1), D_(XIV-2), J_(XIV-1), J_(XIV-2) and K_(XIV-1)are N;

[0616] D_(XIV-3), D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2) areindependently selected from the group consisting of C, N, O, S and acovalent bond with the provisos that no more than one of D_(XIV-3),D_(XLV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2) is a covalent bond, nomore than one of D_(XIV-3), D_(XIV-4), J_(XIV-3), J_(XIV-4) andK_(XIV-2) is O, no more than one of D_(XIV-3), D_(XIV-4), J_(XIV-3),J_(XIV-4) and K_(XIV-2) is S, one of D_(XIV-3), D_(XIV-4), J_(XIV-3),J_(XIV-4) and K_(XIV-2) must be a covalent bond when two of D_(XIV-3),D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2) are O and S, and no morethan four of D_(XIV-3), D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2)and K_(XIV-2) are N;

[0617] R_(XIV-2) is independently selected from the group consisting ofhydrido, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylamino,dialkylamino, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkoxyalkyl,aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl,alkylthioalkyl, aralkylthioalkyl, arylthioalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy,aloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl,dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl,alkylsulfinyl, alkylsulfonyl, alkylsulfinylalkyl, alkylsulfonylalkyl,haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl,arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl,cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl,cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl,heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl,aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide,carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl;

[0618] R_(XIV-2) and R_(XIV-3) are taken together to form a linearspacer moiety selected from the group consisting of a covalent singlebond and a moiety having from 1 through 6 contiguous atoms to form aring selected from the group consisting of a cycloalkyl having from 3through 8 contiguous members, a cycloalkenyl having from 5 through 8contiguous members, and a heterocyclyl having from 4 through 8contiguous members;

[0619] R_(XIV-3) is selected from the group consisting of hydrido,hydroxy, halo, cyano, aryloxy, hydroxyalkyl, amino, alkylamino,dialkylamino, acyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio,alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl,heteroarylthio, aralkylthio, aralkoxyalkyl, alkylsulfinylalkyl,alkylsulfonylalkyl, aroyl, heteroaroyl, aralkylthioalkyl,heteroaralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl,alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl,haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl,monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl,alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl,arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl,aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl,cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl;

[0620] Y_(XIV) is selected from a group consisting of a covalent singlebond,(C(R_(XIV-14))₂)_(qXIV) wherein _(qXIV) is an integer selected from1 and 2 and (CH(R_(XIV-14)))_(gXIV)—W_(XIV)—(CH(R_(XIV-14))) _(pXIV)wherein _(gXIV) and _(pXIV) are integers independently selected from 0and 1;

[0621] R_(XIV-14) is independently selected from the group consisting ofhydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino,hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl,acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl,aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl,alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl,alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl,arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl,haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl,arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma moiety having a chain length of 3 to 6 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-9) and R_(XIV-13)to form a ring selected from the group consisting of a cycloalkenyl ringhaving from 5 through 8 contiguous members and a heterocyclyl ringhaving from 5 through 8 contiguous members and a spacer selected from amoiety having a chain length of 2 to 5 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-4) and R_(XIV-8) toform a heterocyclyl having from 5 through 8 contiguous members with theproviso that, when Y_(XIV) is a covalent bond, an R_(XIV-14) substituentis not attached to Y_(XIV);

[0622] R_(XIV-14) and R_(XIV-14), when bonded to the different atoms,are taken together to form a group selected from the group consisting ofa covalent bond, alkylene, haloalkylene, and a spacer selected from agroup consisting of a moiety having a chain length of 2 to 5 atomsconnected to form a ring selected from the group of a saturatedcycloalkyl having from 5 through 8 contiguous members, a cycloalkenylhaving from 5 through 8 contiguous members, and a heterocyclyl havingfrom 5 through 8 contiguous members;

[0623] R_(XIV-14) and R_(XIV-14), when bonded to the same atom are takentogether to form a group selected from the group consisting of oxo,thiono, alkylene, haloalkylene, and a spacer selected from the groupconsisting of a moiety having a chain length of 3 to 7 atoms connectedto form a ring selected from the group consisting of a cycloalkyl havingfrom 4 through 8 contiguous members, a cycloalkenyl having from 4through 8 contiguous members, and a heterocyclyl having from 4 through 8contiguous members;

[0624] W_(XIV) is selected from the group consisting of O,C(O), C(S),C(O)N(R_(XIV-14)), C(S)N(R_(XIV-14)), (R_(XIV-14))NC(O),(R_(XIV-14))NC(S), S, S(O), S(O)₂, S(O)₂N(R_(XIV-14)),(R_(XIV-14))NS(O)₂, and N(R_(XIV-14)) with the proviso that R_(XIV-14)is selected from other than halo and cyano;

[0625] Z_(XIV) is independently selected from a group consisting of acovalent single bond, (C(R_(XIV-15))₂)_(qXIV-2) wherein _(qXIV-2) is aninteger selected from 1 and 2,(CH(R_(XIV-15)))_(jXIV)—W—(CH(R_(XIV-15)))_(kXIV) wherein _(jXIV) and_(kXIV) are integers independently selected from 0 and 1 with theproviso that, when Z_(XIV) is a covalent single bond, an R_(XIV-15)substituent is not attached to Z_(XIV);

[0626] R_(XIV-15) is independently selected, when Z_(XIV) is(C(R_(XIV-15))₂)_(qXIV) wherein _(qXIV) is an integer selected from 1and 2, from the group consisting of hydrido, hydroxy, halo, cyano,aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl,heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy,alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl,aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl,aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl,heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl,cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl,cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl,haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl,arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma moiety having a chain length of 3 to 6 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-4) and R_(XIV-8) toform a ring selected from the group consisting of a cycloalkenyl ringhaving from 5 through 8 contiguous members and a heterocyclyl ringhaving from 5 through 8 contiguous members, and a spacer selected from amoiety having a chain length of 2 to 5 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-9) and R_(XIV-13)to form a heterocyclyl having from 5 through 8 contiguous members;

[0627] R_(XIV-15) and R_(XIV-15), when bonded to the different atoms,are taken together to form a group selected from the group consisting ofa covalent bond, alkylene, haloalkylene, and a spacer selected from agroup consisting of a moiety having a chain length of 2 to 5 atomsconnected to form a ring selected from the group of a saturatedcycloalkyl having from 5 through 8 contiguous members, a cycloalkenylhaving from 5 through 8 contiguous members, and a heterocyclyl havingfrom 5 through 8 contiguous members;

[0628] R_(XIV-15) and R_(XIV-15), when bonded to the same atom are takentogether to form a group selected from the group consisting of oxo,thiono, alkylene, haloalkylene, and a spacer selected from the groupconsisting of a moiety having a chain length of 3 to 7 atoms connectedto form a ring selected from the group consisting of a cycloalkyl havingfrom 4 through 8 contiguous members, a cycloalkenyl having from 4through 8 contiguous members, and a heterocyclyl having from 4 through 8contiguous members;

[0629] R_(XIV-15) is independently selected, when Z_(XIV) is(CH(R_(XIV-15)))_(jXIV)—W—(CH(R_(XIV-15)))_(kXIV) wherein _(jXIV) and_(kXIV) are integers independently selected from 0 and 1, from the groupconsisting of hydrido, halo, cyano, aryloxy, carboxyl, acyl, aroyl,heteroaroyl, hydroxyalkyl, heteroaryloxyalkyl, acylamido, alkoxy,alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl,aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, aralkoxyalkyl,heteroaralkoxyalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl,alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl,dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl,alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl,arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl,aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma linear moiety having a chain length of 3 to 6 atoms connected to thepoint of bonding selected from the group consisting of R_(XIV-4) andR_(XIV-8) to form a ring selected from the group consisting of acycloalkenyl ring having from 5 through 8 contiguous members and aheterocyclyl ring having from 5 through 8 contiguous members, and aspacer selected from a linear moiety having a chain length of 2 to 5atoms connected to the point of bonding selected from the groupconsisting of R_(XIV-9) and R_(XIV-13) to form a heterocyclyl ringhaving from 5 through 8 contiguous members;

[0630] R_(XIV-4), R_(XIV-5), R_(XIV-6), R_(XIV-7), R_(XIV-8), R_(XIV-9),R_(XIV-10), R_(XIV-11), R_(XIV-12), and R_(XIV-13) are independentlyselected from the group consisting of perhaloaryloxy, alkanoylalkyl,alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy,heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy,alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy,aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido,N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl,cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio,heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy,heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl,heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl,aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio,alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy,cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl,heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl,alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl,lower cycloalkenylalkyl, halo, haloalkyl; haloalkenyl, haloalkoxy,hydroxyhaloalkyl, hydroxyaralkyl, hydroxyaikyl, hydoxyheteroaralkyl,haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl,saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl with the proviso that there are one to fivenon-hydrido ring substituents R_(XIV-4), R_(XIV-5), R_(XIV-6),R_(XIV-7), and R_(XIV-8) present, that there are one to five non-hydridoring substituents R_(XIV-9), R_(XIV-10), R_(XIV-11), R_(XIV-12), andR_(XIV-13) present, and R_(XIV-4), R_(XIV-5), R_(XIV-6), R_(XIV-7),R_(XIV-8), R_(XIV-9), R_(XIV-10), R_(XIV-11), R_(XIV-12), and R_(XIV-13)are each independently selected to maintain the tetravalent nature ofcarbon, trivalent nature of nitrogen, the divalent nature of sulfur, andthe divalent nature of oxygen;

[0631] R_(XIV-4) and R_(XIV-5), R_(XIV-5) and R_(XIV-6), R_(XIV-6) andR_(XIV-7), R_(XIV-7) and R_(XIV-8), R_(XIV-8) and R_(XIV-9), R_(XIV-9)and R_(XIV-10), R_(XIV-10) and R_(XIV-11), R_(XIV-11) and R_(XIV-12),and R_(XIV-12) and R_(XIV-13) are independently selected to form spacerpairs wherein a spacer pair is taken together to form a linear moietyhaving from 3 through 6 contiguous atoms connecting the points ofbonding of said spacer pair members to form a ring selected from thegroup consisting of a cycloalkenyl ring having 5 through 8 contiguousmembers, a partially saturated heterocyclyl ring having 5 through 8contiguous members, a heteroaryl ring having 5 through 6 contiguousmembers, and an aryl with the provisos that no more than one of thegroup consisting of spacer pairs R_(XIV-4) and R_(XIV-5), R_(XIV-5) andR_(XIV-6), R_(XIV-6) and R_(XIV-7), and R_(XIV-7) and R_(XIV-8) are usedat the same time and that no more than one of the group consisting ofspacer pairs R_(XIV-9) and R_(XIV-10), R_(XIV-10) and R_(XIV-11),R_(XIV-11) and R_(XIV-12), and R_(XIV-12) and R_(XIV-13) are used at thesame time;

[0632] R_(XIV-4) and R_(XIV-9), R_(XIV-4) and R_(XIV-13) R_(XIV-8) andR_(XIV-9), and R_(XIV-8) and R_(XIV-13) are independently selected toform a spacer pair wherein said spacer pair is taken together to form alinear moiety wherein said linear moiety forms a ring selected from thegroup consisting of a partially saturated heterocyclyl ring having from5 through 8 contiguous members and a heteroaryl ring having from 5through 6 contiguous members with the proviso that no more than one ofthe group consisting of spacer pairs R_(XIV-4) and R_(XIV-9), R_(XIV-4)and R_(XIV-13), R_(XIV-8) and R_(XIV-9), and R_(XIV-8) and R_(XIV-13) isused at the same time.

[0633] Compounds of Formula XIV and their methods of manufacture aredisclosed in PCT Publication No. WO 00/18721, which is incorporatedherein by reference in its entirety for all purposes.

[0634] In a preferred embodiment, the CETP inhibitor is selected fromthe following compounds of Formula XIV:

[0635]3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0636]3-[[3-(3-isopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0637]3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0638]3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]1,1,1-trifluoro-2-propanol;

[0639]3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0640]3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0641]3-[[3-(4-methlylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0642]3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0643]3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0644] 3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0645]3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0646]3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0647] 3-[[3-(3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0648]3-[[3-(3-t-butylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]1,1,1-trifluoro-2-propanol;

[0649] 3-[[3-(3-methylphenoxy)phenyl]([3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0650]3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0651]3-[[3-(phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0652] 3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0653] 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0654]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0655]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0656]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,-trifluoro-2-propanol;

[0657]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0658]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0659]3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0660]3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0661]3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0662]3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0663]3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyf][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1,-trifluoro-2-propanol;

[0664]3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(pentafluoroethymethyl]amino]-1,1,1-trifluoro-2-propanol;

[0665]3-[[3-(3-isopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0666]3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0667] 3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0668] 3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1 ,1-trifluoro-2-propanol;

[0669]3-[[3-(4-fluorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0670]3-[[3-(4-methylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1 -trifluoro-2-propanol;

[0671]3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0672]3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0673]3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0674]3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1 -trifluoro-2-propanol;

[0675] 3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0676]3-[[3-(3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0677] 3-[[3-(3-t-butylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0678] 3-[[3-(3-methylphenoxy)phenyl][[3-pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0679]3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0680]3-[[3-(phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0681]3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0682]3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0683]3-[[[3-(pentafluoroethyi)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0684]3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0685]3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0686]3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0687]3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;

[0688]3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0689]3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0690] 3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0691]3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0692]3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0693]3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0694] 3-[[3-(3-isopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0695] 3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0696] 3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0697] 3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0698] 3-[[3-(4-fluorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0699] 3-[[3-(4-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0700] 3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifiuoro-2-propanol;

[0701] 3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0702]3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(heptafluoropropyl)-phenyl]methyllamino]-1,1,1-trifluoro-2-propanol;

[0703]3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0704]3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0705]3-[[3-(3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0706]3-[[3-(3-t-butylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0707] 3-[[3-(3-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0708]3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0709]3-[[3-(phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0710]3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0711]3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0712]3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0713]3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0714]3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0715]3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0716]3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;

[0717]3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0718]3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0719] 3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0720]3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0721]3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(heptafluoropropyl)-phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0722]3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0723]3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0724]3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0725]3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0726]3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-5-(trifiuoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0727] 3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0728]3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0729]3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0730]3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0731]3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-5-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0732]3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0733]3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0734] 3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1, 1 ,1-trifluoro-2-propanol;

[0735] 3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0736] 3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0737]3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0738]3-[[3-(phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0739]3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0740]3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0741]3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]methoxy]phenyl]amino]-1,1 -trifluoro-2-propanol;

[0742] 3-[[[2-fluoro-5-(trifluoromethyl )phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0743]3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0744]3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0745]3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1-trifluoro-2-propanol;

[0746]3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0747]3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0748]3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0749]3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0750]3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0751]3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0752]3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0753]3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0754]3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0755]3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0756] 3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0757] 3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0758]3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0759]3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-11,1 ,t1 rifluoro-2-propanol;

[0760]3-[[3-[3-(1,1,2,2-tetrafluorbethoxy)phenoxy]phenyl][[2-fluoro-4-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0761]3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0762]3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0763] 3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]- amino]-1,1,1-trifluoro-2-propanol;

[0764] 3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0765] 3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0766]3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0767] 3-[[3-(phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0768]3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0769]3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0770]3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0771] 3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0772]3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0773]3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0774]3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0775]3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0776]3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0777]3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0778]3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;and

[0779]3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-4-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol.

[0780] Another class of CETP inhibitors that finds utility with thepresent invention consists of substitued N-Aliphatic-N-Aromatictertiary-Heteroalkylamines having the Formula XV

[0781] and pharmaceutically acceptable forms thereof, wherein:

[0782] n_(XV) is an integer selected from 1 through 2;

[0783] A_(XV) and Q_(XV) are independently selected from the groupconsisting of

[0784] with the provisos that one of A_(XV) and Q_(XV) must be AQ-1 andthat one of A_(XV) and Q_(XV) must be selected from the group consistingof AQ-2 and-CH₂(CR_(XV-37)R_(XV-38))_(vXV)-(CR_(XV-3)R_(XV-36))_(uXV)-H;

[0785] T_(XV) is selected from the group consisting of a single covalentbond, O, S, S(O), S(O)₂, C(R_(XV-33))=C(R_(XV-35)), and C≡C;

[0786]_(vXV) is an integer selected from 0 through 1 with the provisothat _(vXV) is 1 when any one of R_(XV-33), R_(XV-34) R_(XV-35), andR_(XV-36) is aryl or heteroaryl;

[0787]_(uXV) and _(wXV) are integers independently selected from 0through 6;

[0788] A_(XV-1) is C(R_(XV-30));

[0789] D_(XV-1), D_(XV-)J_(XV-1), J_(XV-2), and K_(XV-1) areindependently selected from the group consisting of C, N, O, S and acovalent bond with the provisos that no more than one of D_(XV-1),D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1) is a covalent bond, no morethan one of D_(XV-1), D_(XV-2), J_(XV-1), J_(XV-) ₂, and K_(XV-1) is O,no more than one of D_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1)is S, one of D_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1) mustbe a covalent bond when two of D_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2),and K_(XV-1) are O and S, and no more than four of D_(XV-1), D_(XV-2),J_(XV-1), J_(XV-2), and K_(XV-1) are N;

[0790] B_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4)J_(XV-3), J_(XV-4), andK_(XV-2) are independently selected from the group consisting of C,C(R_(XV-30)), N, O, S and a covalent bond with the provisos that no morethan 5 of B_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4),and K_(XV-2) are a covalent bond, no more than two of B_(XV-1),B_(XV-2), D_(XV-3), D_(XV) ₄, J_(XV-3), J_(XV-4), and K_(XV-2) are O, nomore than two of B_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4) J_(XV-3),J_(XV-4), and K_(XV-2) are S, no more than two of B_(XV-1), B_(XV-2),D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4), and K_(XV-2) are simultaneouslyO and S, and no more than two of B_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4),J_(XV-3), J_(XV-4), and K_(XV-2) are N;

[0791] B_(XV-1) and D_(XV-3), D_(XV-3) and J_(XV-3), J_(XV-3) andK_(XV-2), K_(XV-2) and J_(XV-4), J_(XV-4) and D_(XV-4), and D_(XV-4) andB_(XV-2) are independently selected to form an in-ring spacer pairwherein said spacer pair is selected from the group consisting ofC(R_(XV-33))═C(R_(XV-35)) and N═N with the provisos that AQ-2 must be aring of at least five contiguous members, that no more than two of thegroup of said spacer pairs are simultaneously C(R_(XV-33))═C(R_(XV-35))and that no more than one of the group of said spacer pairs can be N═Nunless the other spacer pairs are other than C(R_(XV-33))═C(R_(XV-35)),O, N, and S;

[0792] R_(XV-1) is selected from the group consisting of haloalkyl andhaloalkoxymethyl;

[0793] R_(XV-2) is selected from the group consisting of hydrido, aryl,alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl and heteroaryl;

[0794] R_(XV-3) is selected from the group consisting of hydrido, aryl,alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;

[0795] Y_(XV) is selected from the group consisting of a covalent singlebond, (CH₂)_(q) wherein q is an integer selected from 1 through 2 and(CH₂)—O—(CH₂)_(k) wherein j and k are integers independently selectedfrom 0 through 1;

[0796] Z_(XV) is selected from the group consisting of covalent singlebond, (CH₂)_(q) wherein q is an integer selected from 1 through 2, and(CH₂)—O—(CH₂)_(k) wherein j and k are integers independently selectedfrom 0 through 1;

[0797] R_(XV-4), R_(XV-8), R_(XV-1) and R_(XV-13) are independentlyselected from the group consisting of hydrido, halo, haloalkyl, andalkyl;

[0798] R_(XV-30) is selected from the group consisting of hydrido,alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio,alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl with theproviso that R_(XV-30) is selected to maintain the tetravalent nature ofcarbon, trivalent nature of nitrogen, the divalent nature of sulfur, andthe divalent nature of oxygen;

[0799] R_(XV-30), when bonded to A_(XV-1), is taken together to form anintra-ring linear spacer connecting the A_(XV-1)-carbon at the point ofattachment of R_(XV-30) to the point of bonding of a group selected fromthe group consisting of R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-31), andR_(XV-32) wherein said intra-ring linear spacer is selected from thegroup consisting of a covalent single bond and a spacer moiety havingfrom 1 through 6 contiguous atoms to form a ring selected from the groupconsisting of a cycloalkyl having from 3 through 10 contiguous members,a cycloalkenyl having from 5 through 10 contiguous members, and aheterocyclyl having from 5 through 10 contiguous members;

[0800] R_(XV-30), when bonded to A_(XV-1), is taken together to form anintra-ring branched spacer connecting the A_(XV-1)-carbon at the pointof attachment of R_(XV-30) to the points of bonding of each member ofany one of substituent pairs selected from the group consisting ofsubsitituent pairs R_(XV-10) and R_(XV-11), R_(XV-10) and R_(XV-31),R_(XV-10) and R_(XV-32), R_(XV-10) and R_(XV-12), R_(XV-11) andR_(XV-31), R_(XV-11) and R_(XV-32), R_(XV-11) and R_(XV-12), R_(XV-31)and R_(XV-32), R_(XV-31) and R_(XV-12), and R_(XV-32) and R_(XV-12) andwherein said intra-ring branched spacer is selected to form two ringsselected from the group consisting of cycloalkyl having from 3 through10 contiguous members, cycloalkenyl having from 5 through 10 contiguousmembers, and heterocyclyl having from 5 through 10 contiguous members;

[0801] R_(XV-4), R_(XV-5), R_(XV-6), R_(XV-7), R_(XV-8), R_(XV-9),R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-13), R_(XV-31), R_(XV-32),R_(XV-33), RXv-₃₄, R_(XV-35), and R_(XV-36) are independently selectedfrom the group consisting of hydrido, carboxy, heteroaralkylthio,heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy,heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl,heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl,aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio,alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy,cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl,heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl,alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl,lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy,hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl,haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl,saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,alkylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl with the provisos that R_(XV-4), R_(XV-5),R_(XV-6), R_(XV-7), R_(XV-8), R_(XV-9), R_(XV-10), R_(XV-11), R_(XV-12),R_(XV-13), R_(XV-31), R_(XV-32), R_(XV-33), R_(XV-34), R_(XV-35), andR_(XV-36) are each independently selected to maintain the tetravalentnature of carbon, trivalent nature of nitrogen, the divalent nature ofsulfur, and the divalent nature of oxygen, that no more than three ofthe R_(XV-33) and R_(XV-34) substituents are simultaneously selectedfrom other than the group consisting of hydrido and halo, and that nomore than three of the R_(XV-35) and R_(XV-36) substituents aresimultaneously selected from other than the group consisting of hydridoand halo;

[0802] R_(XV-9) , R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-13), R_(XV-31),and R_(XV-32) are independently selected to be oxo with the provisosthat B_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4), andK_(XV-2) are independently selected from the group consisting of C andS, no more than two of R_(XV-9), R_(XV-10), R_(XV-11), R_(XV-12),R_(XV-13), R_(XV-31), and R_(XV-32) are simultaneously oxo, and thatR_(XV-9), R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-13), R_(XV-31), andR_(XV-32) are each independently selected to maintain the tetravalentnature of carbon, trivalent nature of nitrogen, the divalent nature ofsulfur, and the divalent nature of oxygen;

[0803] R_(XV-4) and R_(XV-5), R_(XV-5) and R_(XV-6), R_(XV-6) andR_(XV-7), R_(XV-7) and R_(XV-8), R_(XV-9) and R_(XV-10), RXv-₁₀ andR_(XV-11), R_(XV-11) and R_(XV-31), R_(XV) ₃₁ and R_(XV-32), R_(XV-32)and R_(XV-12), and R_(XV-12) and R_(XV-13) are independently selected toform spacer pairs wherein a spacer pair is taken together to form alinear moiety having from 3 through 6 contiguous atoms connecting thepoints of bonding of said spacer pair members to form a ring selectedfrom the group consisting of a cycloalkenyl ring having 5 through 8contiguous members, a partially saturated heterocyclyl ring having 5through 8 contiguous members, a heteroaryl ring having 5 through 6contiguous members, and an aryl with the provisos that no more than oneof the group consisting of spacer pairs R_(XV-4) and R_(XV-5), R_(XV-5)and R_(XV-6), R_(XV-6) and R_(XV-7), R_(XV-7) and R_(XV-8) is used atthe same time and that no more than one of the group consisting ofspacer pairs R_(XV-9) and R_(XV-10), R_(XV-10) and R_(XV-11), R_(XV-11)and R_(XV-31), R_(XV-31) and R_(XV-32), R_(XV-32) and R_(XV-12), andR_(XV-12) and R_(XV-13) are used at the same time;

[0804] R_(XV-9) and R_(XV-11), R_(XV-9) and R_(XV-12), R_(XV-9) andR_(XV-13) R_(XV-9) and R_(XV-31), R_(XV-32) and R_(XV-32), R_(XV-10) andR_(XV-12), R_(XV-10) and R_(XV-13), R_(XV-10) and R_(XV-31),R_(XV-lo and R) _(XV-32), R_(XV-11), and R_(XV-12), R_(XV-11) andR_(XV-13), R_(XV-11) and R_(XV-32), R_(XV-12) and R_(XV-31), R_(XV-13)and R_(XV-31), and R_(XV-13) and R_(XV-32) are independently selected toform a spacer pair wherein said spacer pair is taken together to form alinear spacer moiety selected from the group consisting of a covalentsingle bond and a moiety having from 1 through 3 contiguous atoms toform a ring selected from the group consisting of a cycloalkyl havingfrom 3 through 8 contiguous members, a cycloalkenyl having from 5through 8 contiguous members, a saturated heterocyclyl having from 5through 8 contiguous members and a partially saturated heterocyclylhaving from 5 through 8 contiguous members with the provisos that nomore than one of said group of spacer pairs is used at the same time;

[0805] R_(XV-37) and R_(XV-38) are independently selected from the groupconsisting of hydrido, alkoxy, alkoxyalkyl, hydroxy, amino, thio, halo,haloalkyl, alkylamino, alkylthio, alkylthioalkyl, cyano, alkyl, alkenyl,haloalkoxy, and haloalkoxyalkyl.

[0806] Compounds of Formula XV and their methods of manufacture aredisclosed in PCT Publication No. WO 00/18723, which is incorporatedherein by reference in its entirety for all purposes.

[0807] In a preferred embodiment, the CETP inhibitor is selected fromthe following compounds of Formula XV:

[0808] 3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0809]3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0810]3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0811]3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-trifiuoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0812] 3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0813] 3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0814]3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)cyclo-hexylmethyl]amino]-1,1,1-trifluoro-2-propanol;

[0815]3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0816]3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0817]3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0818]3-[[3-(3-trifluoromethoxyphenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyllamino]-l1,1,1-trifluoro-2-propanol;

[0819]3-[[3-(3-trifluoromethoxyphenoxy)phenyl]](3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0820]3-[[3-(3-trifluoromethoxyphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0821]3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0822]3-[[3-(3-isopropylphenoxy)phenyl](cyclohexylmethyl]amino]-1,1,1-trifiuoro-2-propanol:

[0823]3-[[3-(3-isopropylphenoxy)phenyl](cyclopentylmethyl]amino]-1,1,1-trifluoro-2-propanol;

[0824]3-[[3-(3-isopropylphenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0825]3-[[3-(3-isopropylphenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0826]3-[[3-(3-isopropylphenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0827]3-[[3-(3-isopropylphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0828]3-[[3-(3-isopropylphenoxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0829] 3-[[3-(2,3-dichlorophenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0830]3-[[3-(2,3-dichlorophenoxy)phenyll(cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0831]3-[[3-(2,3-dichlorophenoxy)phenyl](cyclopropylmethy)amino]-1,1,1-trifluoro-2-propanol;

[0832]3-[[3-(2,3-dichlorophenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0833]3-[[3-(2,3-dichlorophenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0834]3-[[3-(2,3-dichlorophenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0835]3-[[3-(2,3-dichlorophenoxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0836]3-[[3-(4-fluorophenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0837]3-[[3-(4-fluorophenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0838]3-[[3-(4-fluorophenoxy)phennyl](cyclopropylmethyl)amino]-,1,1,1-triflouro-2-propanol;

[0839] 3-[[3-(4-fluorophenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0840] 3-[[3-(4-fluorophenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0841] 3-[[3-(4-fluorophenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0842]3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0843]-[[3-(3-trifluoromethoxybenzyloxy]phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0844]3-[[3-(3-trifluoromethoxybenzyloxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0845]3-[[3-(3-trifluoromethoxybenzyloxy)phenyl](cyclopropylmethyl]amino]-1,1,1-trifluoro-2-propanol;

[0846]3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0847]3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0848]3-[[3-(3-trifluoromethoxybenzyloxy]phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0849]3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)-cyclohexylmethyl]amino]-1,1,1-trifluoro-2-propanol;

[0850]3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclohexylmethyl)aminol-1,1,1-trifluoro-2-propanol;

[0851]3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0852]3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0853]3-[[3-(3-trifluoromethylbenzyloxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-proplanol;

[0854]3-[[3-(3-trifluoromethylbenzyloxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0855]3-[[3-(3-trifluoromethylbenzyloxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0856]3-[[3-(3-trifluoromethylbenzyloxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0857]3-[[[(3-trifluoromethyl)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0858]3-[[[(3-pentafluoroethyl)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0859] 3-[[[(3-trifluoromethoxy)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0860]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0861]3-[[[(3-trifluoromethyl)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0862]3-[[[(3-pentafluoroethyl)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0863]3-[[[(3-trifluoromethoxy)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0864]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0865]3-[[[(3-trifluoromethyl]phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0866]3-[[[(3-pentafluoroethyl)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0867]3-[[[(3-trifluoromethoxy)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0868]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0869]3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;

[0870]3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;

[0871]3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-methylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;

[0872]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-cyclohexyl]amino]-1,1,1-trifluoro-2-propanol;

[0873]3-[[[(3-trifluoromethyl]phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0874]3-[[[(3-pentafluoroethyl)phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0875]3-[[[(3-trifluoromethoxy)phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0876]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0877]3-[[[(3-trifloromethyl)phenyl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0878]3-[[[(3-pentafluoroethyl)phenyl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0879]3-[[[(3-trifluoromethoxy)phenyl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0880]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-isopropoxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;

[0881]3-[[[(3-trifluoromethyl)phenyl]methyl](3-cyclopentyloxycyclohexyl]amino]-1,1,1-trifluoro-2-propanol;

[0882]3-[[[(3-pentafluoroethyl]phenyl]methyl](3-cyclopentyloxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0883]3-[[[(3-trifluoromethoxy)phenyl]methyl](3-cyclopentyloxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0884]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-cyclopentyloxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;

[0885]3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0886]3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-cyclopentyloxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;

[0887]3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0888]3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0889]3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;

[0890]3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl][3-(1,1,2,2-tetrafluoroethoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;

[0891]3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-pentafluoroethylcyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;

[0892]3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-trifluoromethoxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;

[0893]3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)propyl]-amino]-1,1,1-trifluoro-2-propanol;

[0894]3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)propyl]-amino]-1,1,1-trifluoro-2-propanol;

[0895]3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)propyl]-amino]-1,1,1-trifluoro-2-propanol;

[0896]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-propyl]amino]-1,1,1-trifluoro-2-propanol;

[0897]3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-di-fluropropyl]amino]-1,1,1-trifluoro-2-propanol;

[0898]3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2-di-fluropropyl]amino]-1,1,1-trifluoro-2-propanol;

[0899]3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-di-fluropropyl]amino]-1,1,1-trifluoro-2-propanol;

[0900]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-difluropropyl]amino]-1,1,1-trifluoro-2-propanol;

[0901]3-[[[(3-trifluoromethyl)phenyl]methyl][3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;

[0902]3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;

[0903]3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;

[0904]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]]3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;and

[0905]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(phenoxy)propyl]amino]-1,1,1-trifluoro-2-propanol.

[0906] Another class of CETP inhibitors that finds utility with thepresent invention consists of (R)-chiral halogenated 1-substitutedamino-(n+l)-alkanols having the Formula XVI

[0907] and pharmaceutically acceptable forms thereof, wherein:

[0908] n_(XVI) is an integer selected from 1 through 4;

[0909] X_(XVI) is oxy;

[0910] R_(XVI-1) is selected from the group consisting of haloalkyl,haloalkenyl, haloalkoxymethyl, and haloalkenyloxymethyl with the provisothat R_(XV) _(XVI-1) has a higher Cahn-Ingold-Prelog stereochemicalsystem ranking than both R_(XVI-2) and(CHR_(XVI-3))_(n)-N(A_(XVI))Q_(XVI) wherein A_(XVI) is Formula XVI-(II)and Q is Formula XVI-(II);

[0911] R_(XVI-16) is selected from the group consisting of hydrido,alkyl, acyl, aroyl, heteroaroyl, trialkylsilyl, and a spacer selectedfrom the group consisting of a covalent single bond and a linear spacermoiety having a chain length of 1 to 4 atoms linked to the point ofbonding of any aromatic substituent selected from the group consistingof R_(XVI-4), R_(XVI-8), R_(XVI-9), and R_(XVI-13) to form aheterocyclyl ring having from 5 through 10 contiguous members;

[0912] D_(XVI-1) D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1) areindependently selected from the group consisting of C, N, O, S andcovalent bond with the provisos that no more than one of D_(XVI-1),D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1) is a covalent bond, nomore than one D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1)is be O, no more than one of D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2)and K_(XVI-1) is S, one of D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2)and K_(XVI-1) must be a covalent bond when two of D_(XVI-1), D_(XVI-2),J_(XVI-1), J_(XVI-2) and K_(XVI-1) are O and S, and no more than four ofD_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1) is N;

[0913] D_(XVI-3), D_(XVI-4), J_(XVI-3), J_(XVI-4) and K_(XVI-2) areindependently selected from the group consisting of C, N, O, S andcovalent bond with the provisos that no more than one is a covalentbond, no more than one of D_(XVI-3), D_(XVI-4), J_(XVI-3), J_(XVI-4) andK_(XVI-2) is O, no more than one of D_(XVI-3), D_(XVI-4), J_(XVI-3),J_(XVI-4) and K_(XVI-2) is S, no more than two of D_(XVI-3), D_(XVI-4),J_(XVI-3), J_(XVI-4) and K_(XVI-2) is 0 and S, one of D_(XVI-3),D_(XVI-4), J_(XVI-3), J_(XVI-4) and K_(XVI-2) must be a covalent bondwhen two of D_(XVI-3), D_(XVI-4), J_(XVI-3), J_(XVI-4) and K_(XVI-2) areO and S, and no more than four of D_(XVI-3), D_(XVI-4), J_(XVI-3),J_(XVI-4) and K_(XVI-2) are N;

[0914] R_(XVI-2) is selected from the group consisting of hydrido, aryl,aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl,halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl,perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, andcarboalkoxycyanoalkyl, with the proviso that R_(XVI-2) has a lowerCahn-lngold-Prelog system ranking than both R_(XVI-1) and(CHR_(XVI-3))_(n)-N(A_(XVI))Q_(XVI);

[0915] R_(XVI-3) is selected from the group consisting of hydrido,hydroxy, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl,alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl,haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl,dicyanoalkyl, carboxamide, and carboxamidoalkyl, with the provisos that(CHR_(XVI-3))_(n)-N(A_(XVI))Q_(XVI) has a lower Cahn-lngold-Prelogstereochemical system ranking than R_(XVI-1) and a higherCahn-lngold-Prelog stereochemical system ranking than R_(XVI-2);

[0916] Y_(XVI) is selected from a group consisting of a covalent singlebond, (C(R_(XVI-14))₂)_(q) wherein q is an integer selected from 1 and 2and (CH(R_(XVI-14)))₉-W_(XVI)-(CH(R_(XVI-14)))_(p) wherein g and p areintegers independently selected from 0 and 1;

[0917] R_(XVI-14) is selected from the group consisting of hydrido,hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl,alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

[0918] Z_(XVI) is selected from a group consisting of a covalent singlebond, (C(R_(XVI-15))₂)_(q), wherein q is an integer selected from 1 and2, and (CH(R_(XVI-15)))_(j)-W_(XVI)-(CH(R_(XVI-15)))_(k) wherein j and kare integers independently selected from 0 and 1;

[0919] W_(XVI) is selected from the group consisting of O, C(O),C(S),C(O)N(R_(XVI-14)), C(S)N(R_(XVI-14)),(R_(XVI-14))NC(O), (R_(XVI-14))NC(S), S, S(O), S(O)₂, S(O)₂N(R_(XVI-14)), (R_(XVI-14))NS(O)₂, andN(R_(XVI-14)) with the proviso that R_(XVI-14) is other than cyano;

[0920] R_(XVI-15) is selected, from the group consisting of hydrido,cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl,haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

[0921] R_(XVI-4), R_(XVI-5), R_(XVI-6), R_(XVI-8), R_(XVI-9),R_(XVI-10), R_(XVI-11), R_(XVI-12), and R_(XVI-13) are independentlyselected from the group consisting of hydrido, carboxy,heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl,acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl,aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl,aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl,halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl,cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl,heteroarylamino, N-heteroarylamino-N-alkylamino, heteroaralkyl,heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl,haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy,cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl,cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl,halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio,nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino,aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl,alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl,heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl,alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl,alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkyl, amidosulfonyl, monoarylamidosulfonyl,arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl,arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl,heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl,alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl,haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky,alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl,cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo,haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl,hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl,heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturatedheterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl with the proviso that R_(XVI-4), R_(XVI-5),R_(XVI-6), R_(XVI-7), R_(XVI-8), R_(XVI-9), R_(XVI-10), R_(XVI-11),R_(XVI-12), and R_(XVI-13) are each independently selected to maintainthe tetravalent nature of carbon, trivalent nature of nitrogen, thedivalent nature of sulfur, and the divalent nature of oxygen;

[0922] R_(XVI-4) and R_(XVI-5), R_(XVI-5) and R_(XVI-6), R_(XVI-6) andR_(XV-7), R_(XVI-7) and R_(XVI-8,)R_(XVI-9) and R_(XVI-10), R_(XVI-10)and R_(XVI-11), R_(XVI-11) and R_(XVI-12) and R_(XVI-12) and R_(XIV-13)are independently selected to form spacer pairs wherein a spacer pair istaken together to form a linear moiety having from 3 through 6contiguous atoms connecting the points of bonding of said spacer pairmembers to form a ring selected from the group consisting of acycloalkenyl ring having 5 through 8 contiguous members, a partiallysaturated heterocyclyl ring having 5 through 8 contiguous members, aheteroaryl ring having 5 through 6 contiguous members, and an aryl withthe provisos that no more than one of the group consisting of spacerpairs R_(XVI-4) and R_(XVI-5), R_(XVI-5) and R_(XVI-6), R_(XVI-6) andR_(XVI-7), and R_(XVI-7) and R_(XVI-8) is used at the same time and thatno more than one of the group consisting of spacer pairs R_(XIV-9) andR_(XVI-10), R_(XVI-10) and R_(XVI-11), R_(XVI-11) and R_(XVI-12), andR_(XVI-12) and R_(XVI-13) can be used at the same time;

[0923] R_(XVI-4) and R_(XVI-9), R_(XVI-4) and R_(XVI-13), R_(XVI-8) andR_(XVI-9), and R_(XVI-8) and R_(XVI-13) is independently selected toform a spacer pair wherein said spacer pair is taken together to form alinear moiety wherein said linear moiety forms a ring selected from thegroup consisting of a partially saturated heterocyclyl ring having from5 through 8 contiguous members and a heteroaryl ring having from 5through 6 contiguous members with the proviso that no more than one ofthe group consisting of spacer pairs R_(XVI-4) and R_(XVI-9), R_(XVI-4)and R_(XVI-13), R_(XVI-8) and R_(XVI-9), and R_(XVI-8) and R_(XVI-13) isused at the same time.

[0924] Compounds of Formula XVI and their methods of manufacture aredisclosed in PCT Publication No. WO 00/18724, which is incorporatedherein by reference in its entirety for all purposes.

[0925] In a preferred embodiment, the CETP inhibitor is selected fromthe following compounds of Formula XVI:

[0926](2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0927](2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0928](2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0929](2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0930](2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0931](2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0932](2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0933](2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0934](2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0935](2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0936](2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0937](2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0938](2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0939](2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol:

[0940](2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0941](2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0942](2R)-3-[[3-(phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0943](2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0944](2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0945](2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoro-methyl)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0946](2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0947](2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0948](2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0949](2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0950](2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0951](2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0952](2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0953](2R)-3-[[[3-(3-trifuoromethylthio)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0954](2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0955](2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0956](2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0957](2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0958](2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0959](2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(pentafluoroethyi)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0960](2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0961](2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0962](2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0963](2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0964](2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0965](2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0966] (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0967] (2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0968] (2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0969] (2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0970](2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0971] (2R)-3-[[3-(phenoxy)phenyl][[3(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0972](2R)-3-[[3-[3-(N,N-dimethylamino)phenoxylphenyl][[3(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0973](2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0974](2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0975](2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0976](2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0977](2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0978](2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;

[0979](2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0980](2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0981](2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0982](2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0983](2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0984](2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0985](2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0986](2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0987] (2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0988] (2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0989] (2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0990] (2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0991](2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0992](2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0993](2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(heptafluoropropyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0994](2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0995] (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0996] (2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0997] (2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0998] (2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0999](2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1000] (2R)-3-[[3-(phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1001] (2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1002](2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1003](2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1004](2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1005](2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1006](2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1007](2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl](3-[cyclohexylmethoxylphenyl]-amino]-1,1,1-trifluoro-2-propanol;

[1008](2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-l1, 1 -trifluoro-2-propanol;

[1009](2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1010](2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1011](2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1012](2R)-3-[(3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(heptafluoropropyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1013](2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1014](2R)-3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1015](2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1016](2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1017](2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1018](2R)-3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-3-propanol;

[1019](2R)-3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1020](2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1021](2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1022](2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-5-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1023](2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1024](2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1025](2R)-3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[1026](2R)-3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[1027](2R)-3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[1028](2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1029] (2R)-3-[[3-(phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1030] (2R)-3-[[3-[3-(N,N-dimethylamino,phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1031](2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-3-propanol;

[1032](2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1033](2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1034](2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1035](2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1036](2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1037](2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1038](2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1039](2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1040](2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1041](2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-5-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1042](2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1043](2R)-3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1044](2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[2-flouro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1045](2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1046](2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1047](2R)-3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1048](2R)-3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1049](2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1050](2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1051](2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1052](2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1053](2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1054](2R)-3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[1055](2R)-3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[1056](2R)-3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[1057](2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1058] (2R)-3-[[3-(phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1059](2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1060](2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1061](3R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1062](2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1063](2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1064](2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1065](2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1066](2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1067](2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1068](2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1069](2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;and

[1070](2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol.

[1071] Another class of CETP inhibitors that finds utility with thepresent invention consists of quinolines of Formula XVII

[1072] and pharmaceutically acceptable forms thereof, wherein:

[1073] A_(XVII) denotes an aryl containing 6 to 10 carbon atoms, whichis optionally substituted with up to five identical or differentsubstituents in the form of a halogen, nitro, hydroxyl, trifluoromethyl,trifluoromethoxy or a straight-chain or branched alkyl, acyl,hydroxyalkyl or alkoxy containing up to 7 carbon atoms each, or in theform of a group according to the formula —NR_(XVII-4)R_(XVII-5), wherein

[1074] R_(XVII-4) and R_(XVII-5) are identical or different and denote ahydrogen, phenyl or a straight-chain or branched alkyl containing up to6 carbon atoms,

[1075] D_(XVII) denotes an aryl containing 6 to 10 carbon atoms, whichis optionally substituted with a phenyl, nitro, halogen, trifluoromethylor trifluoromethoxy, or a radical according to the formula

[1076] wherein

[1077] R_(XVII-6), R_(XVII-7), R_(XVII-10) denote, independently fromone another, a cycloalkyl containing 3 to 6 carbon atoms, or an arylcontaining 6 to 10 carbon atom or a 5- to 7-membered, optionallybenzo-condensed, saturated or unsaturated, mono-, bi- or tricyclicheterocycle containing up to 4 heteroatoms from the series of S, Nand/or O, wherein the rings are optionally substituted, in the case ofthe nitrogen-containing rings also via the N function, with up to fiveidentical or different substituents in the form of a halogen,trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, astraight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxyor alkoxycarbonyl containing up to 6 carbon atoms each, an aryl ortrifluoromethyl-substituted aryl containing 6 to 10 carbon atoms each,or an optionally benzo-condensed, aromatic 5- to 7-membered heterocyclecontaining up to 3 heteoatoms from the series of S, N and/or O, and/orin the form of a group according to the formula —OR_(XVII-11),—SR_(XVII-12), —SO₂R_(XVII-13), or —NR_(XVII-14)R_(XVII-15);

[1078] R_(XVII-11), R_(XVII-12), and R_(XVII-13) denote, independentlyfrom one another, an aryl containing 6 to 10 carbon atoms, which is inturn substituted with up to two identical or different substituents inthe form of a phenyl, halogen or a straight-chain or branched alkylcontaining up to 6 carbon atoms,

[1079] R_(XVII-14) and R_(XVII-15) are identical or different and havethe meaning of R_(XVII-4) and R_(XVII-5) given above, or

[1080] R_(XVII-6) and/or R_(XVII-7) denote a radical according to theformula

[1081] R_(XVII-8) denotes a hydrogen or halogen, and

[1082] R_(XVII-9) denotes a hydrogen, halogen, azido, trifluoromethyl,hydroxyl, trifluoromethoxy, a straight-chain or branched alkoxy or alkylcontaining up to 6 carbon atoms each, or a radical according to theformula NR_(XVII-16)R_(XVII-17),

[1083] R_(XVII-16) and R_(XVII-17) are identical or different and havethe meaning of R_(XVII-4) and R_(XVII-5) above; or

[1084] R_(XVII-8) and R_(XVIl) ₉ together form a radical according tothe formula ═O or ═NR_(XVII-18);

[1085] R_(XVII-18) denotes a hydrogen or a straight-chain or branchedalkyl, alkoxy or acyl containing up to 6 carbon atoms each;

[1086] L_(XVII) denotes a straight-chain or branched alkylene oralkenylene chain containing up to 8 carbon atoms each, which areoptionally substituted with up to two hydroxyl groups;

[1087] T_(XVII) and X_(XVII) are identical or different and denote astraight-chain or branched alkylene chain containing up to 8 carbonatoms; or

[1088] T_(XVII) and X_(XVII) denotes a bond;

[1089] V_(XVII) denotes an oxygen or sulfur atom or —NR_(XVII-19);

[1090] R_(XVII-19) denotes a hydrogen or a straight-chain or branchedalkyl containing up to 6 carbon atoms or a phenyl;

[1091] E_(XVII) denotes a cycloalkyl containing 3 to 8 carbon atoms, ora straight-chain or branched alkyl containing up to 8 carbon atoms,which is optionally substituted with a cycloalkyl containing 3 to 8carbon atoms or a hydroxyl, or a phenyl, which is optionally substitutedwith a halogen or trifluoromethyl;

[1092] R_(XVII-1) and R_(XVII-2) are identical or different and denote acycloalkyl containing 3 to 8 carbon atoms, hydrogen, nitro, halogen,trifluoromethyl, trifluoromethoxy, carboxy, hydroxy, cyano, astraight-chain or branched acyl, alkoxycarbonyl or alkoxy with up to 6carbon atoms, or NR_(XVII-20)R_(XVII-21);

[1093] R_(XVII-20) and R_(XVII-21) are identical or different and denotehydrogen, phenyl, or a straight-chain or branched alkyl with up to 6carbon atoms; and or

[1094] R_(XVII-1) and/or R_(XVII-2) are straight-chain or branched alkylwith up to 6 carbon atoms, optionally substituted with halogen,trifluoromethoxy, hydroxy, or a straight-chain or branched alkoxy withup to 4 carbon atoms, aryl containing 6-10 carbon atoms optionallysubstituted with up to five of the same or different substituentsselected from halogen, cyano, hydroxy, trifluoromethyl,trifluoromethoxy, nitro, straight-chain or branched alkyl, acyl,hydroxyalkyl, alkoxy with up to 7 carbon atoms andNR_(XVII-22)R_(XVII-23);

[1095] R_(XVII-22) and R_(XVII-23) are identical or different and denotehydrogen, phenyl or a straight-chain or branched akyl up to 6 carbonatoms; and/or

[1096] R_(XVII-1) and R_(XVII-2) taken together form a straight-chain orbranched alkene or alkane with up to 6 carbon atoms optionallysubstituted with halogen, trifluoromethyl, hydroxy or straight-chain orbranched alkoxy with up to 5 carbon atoms;

[1097] R_(XVII-3) denotes hydrogen, a straight-chain or branched acylwith up to 20 carbon atoms, a benzoyl optionally substituted withhalogen, trifluoromethyl, nitro or trifluoromethoxy, a straight-chainedor branched fluoroacyl with up to 8 carbon atoms and 7 fluoro atoms, acycloalkyl with 3 to 7 carbon atoms, a straight chained or branchedalkyl with up to 8 carbon atoms optionally substituted with hydroxyl, astraight-chained or branched alkoxy with up to 6 carbon atoms optionallysubstituted with phenyl which may in turn be substituted with halogen,nitro, trifluoromethyl, trifluoromethoxy, or phenyl or a tetrazolsubstitued phenyl, and/or an alkyl that is optionally substituted with agroup according to the formula —OR_(XVII-24);

[1098] R_(XVII-24) is a straight-chained or branched acyl with up to 4carbon atoms or benzyl.

[1099] Compounds of Formula XVII and their methods of manufacture aredisclosed in PCT Publication No. WO 98/39299, which is incorporatedherein by reference in its entirety for all purposes.

[1100] Another class of CETP inhibitors that finds utility with thepresent invention consists of 4-Phenyltetrahydroquinolines of FormulaXVIII

[1101] N oxides thereof, and pharmaceutically acceptable forms thereof,wherein:

[1102] A_(XVIII) denotes a phenyl optionally substituted with up to twoidentical or different substituents in the form of halogen,trifluoromethyl or a straight-chain or branched alkyl or alkoxycontaining up to three carbon atoms;

[1103] D_(XVIII), denotes the formula

[1104] or R_(VIII-5)—CH₂—O—CH₂ —;

[1105] R_(XVIII-5) and R_(XVIII-6) are taken together to form ═O; or

[1106] R_(XVIII-5) denotes hydrogen and R_(XVII-6) denotes halogen orhydrogen; or

[1107] R_(XVIII-5) and R_(XVIII-6) denote hydrogen;

[1108] R_(XVIII-7) and R_(XVIII-8) are identical or different and denotephenyl, naphthyl, benzothiazolyl, quinolinyl, pyrimidyl or pyridyl withup to four identical or different substituents in the form of halogen,trifluoromethyl, nitro, cyano, trifluoromethoxy, —SO₂—CH₃ orNR_(XVIII-9)R_(XVIII-10);

[1109] R_(XVIII-9) and R_(XVII-10) are identical or different and denotehydrogen or a straight-chained or branched alkyl of up to three carbonatoms;

[1110] E_(XVIII) denotes a cycloalkyl of from three to six carbon atomsor a straight-chained or branched alkyl of up to eight carbon atoms;

[1111] R_(XVIII-1) denotes hydroxy;

[1112] R_(XVIII-2) denotes hydrogen or methyl;

[1113] R_(XVIII-3) and R_(XVIII-4) are identical or different and denotestraight-chained or branched alkyl of up to three carbon atoms; or

[1114] R_(XVIII-3) and R_(XVIII-4) taken together form an alkenylenemade up of between two and four carbon atoms.

[1115] Compounds of Formula XVIII and their methods of manufacture aredisclosed in PCT Publication No. WO 99/15504 and U.S. Pat. No.6,291,477, both of which are incorporated herein by reference in theirentireties for all purposes.

[1116] The present invention is particularly advantageous for the classof drugs which are both acid-sensitive and low-solubility. Exemplaryacid-sensitive, low-solubility drugs include(+)-N-{3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl}-N-hydroxyurea;omeprazole; etoposide; famotidine; erythromycin; quinapril;lansoprazole; progabide; as well as CCR1 inhibitors such asquinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-3-fluorobenzyl-2(S),7-dihydroxy-7-methyl-octyl]amideand quinoxaline-2-carboxylic acid[1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide.

[1117] The invention is useful for improving the intrinsic dissolutionrate of compounds selected from the following. The intrinsic dissolutionrate is defined as the rate of dissolution of a pure pharmaceuticalactive ingredient when conditions such as surface area,agitation-stirring speed, pH and ionic-strength of the dissolutionmedium are kept constant. Intrinsic dissolution rate is further definedas being measured in water at 37° C. using a USP II dissolutionapparatus equipped with a Wood's apparatus (Wood, J H; Syarto, J E andLetterman, H: J.Pharm. Sci. 54 (1965), 1068) with a stirring speed of 50rpm. The intrinsic dissolution rate is defined in terms of mg of drugdissolved per minute from a unit surface area, therefore, the intrinsicdissolution rate is referred to in units of mg/min.cm².

[1118] The compositions and methods of the invention are particularlyuseful for compounds with an intrinsic dissolution rate of preferablyless than 0.1 mg/min.cm² and more preferably with less than 0.05mg/min.cm².

[1119] Turning now to the chemical structures of specific CCR1inhibitors, one class of CCR1 inhibitors that finds utility with thepresent invention consists of dihydroxyhexanoic acid derivatives havingthe Formula CCR1-1

[1120] wherein R¹ is (C₂-C₉) heteroaryl optionally substituted with one,two or three substituents independently selected from the groupconsisting of hydrogen, halo, cyano, (C₁-C₆)alkyl optionally substitutedwith one, two or three fluorine atoms, hydroxy, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—,(C₁-C₆)alkyl—O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O-,(C₁-C₆)alkyl-(C═O)—O-(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl—SO₂—, (C₁-C₆)alkyl—SO₂-NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂-(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂-(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

[1121] wherein R₂ is phenyl-(CH₂)_(m)—, naphthyl-(CH₂)_(m)—,(C₃-C₁₀)cycloalkyl- (CH₂)_(m)—, (C₁-C₆)alkyl or(C₂-C₉)heteroaryl-(CH₂)_(m)—, wherein each of said phenyl, naphthyl,(C₃-C₁₀)cycloalkyl or (C₂-C₉)heteroaryl moieties of said phenyl-(CH₂)_(m)—, naphthyl-(CH₂)_(m)—, (C₃-C₁₀)cycloalkyl-(CH₂)m- or(C₂-C₉)heteroaryl-(CH₂)_(m) groups may optionally be substituted withone, two, or three substituents independently selected from the groupconsisting of hydrogen, halo, cyano, (C₁-C₆)alkyl, hydroxy,hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)-(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O-(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl—SO₂—, (C₁-C₆)alkyl—SO₂-NH—, H₂N—SO₂—,H₂N—SO₂-(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂-(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂-(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl—SO₃—, phenyl,phenoxy, benzyloxy, (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and(C₂-C₉)heteroaryl;

[1122] wherein R₃ is hydrogen, (C₁-C₁₀ )alkyl,(C₃-C₁₀)cycloalkyl-(CH₂)_(n)—, (C₂-C₉)heterocycloalkyl-(CH₂)_(n)—,(C₂-C₉)heteroaryl-(CH₂),- or aryl-(CH₂)_(n)—; wherein n is an intergerfrom zero to six;

[1123] wherein said R₃ (C₁-C₁₀)alkyl group may optionally be substitutedwith one or more substituents, (preferably from one to threesubstituents) independently selected from hydrogen, halo, CN,(C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl, (C0-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O-(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl—SO₂—, (C₁-C₆)alkyl—SO₂-NH—, H₂N—SO₂—,H₂N—SO₂-(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂-(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂N—SO₂-(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl—SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl; andwherein any of the carbon-carbon single bonds of said (C₁-C₁₀)alkyl mayoptionally be replaced by a carbon-carbon double bond;

[1124] wherein the (C₃-C₁₀)cycloalkyl moiety of said R₃(C₃-C₁₀)cycloalkyl-(CH₂)_(n)— group may optionally be substituted by oneto three substitutents independently selected from the group consistingof hydrogen, halo, CN, (C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O-(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl—SO₂—, (C₁-C₆)alkyl—SO₂-NH—, H₂N—SO₂—,H₂N—SO₂-(C₁-C₆)alkyl, (C₁-C₆)alkyl HN—SO₂-(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂-(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl—SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

[1125] wherein the (C₂-C₉)heterocycloalkyl moiety of said R₃(C₂-C₉)heterocycloalkyl-(CH₂)_(n)— group may contain from one to threeheteroatoms independently selected from nitrogen, sulfur,oxygen, >S(═O), >SO₂ or >NR⁶, wherein said (C₂-C₉)heterocycloalkylmoiety of said (C₂-C₉)heterocycloalkyl-(CH₂)_(n)— group may optionallybe substituted on any of the ring carbon atoms capable of forming anadditional bond (preferably one to three substitutents per ring) with asubstituent independently selected from the group consisting ofhydrogen, halo, CN, (C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O-(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[N H](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl—SO₂—, (C₁-C₆)alkyl—SO₂-NH—, H₂N—SO₂—,H₂N—SO₂-(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂-(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂-(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl—SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

[1126] wherein the (C₂-C₉)heteroaryl moiety of said R³(C₂-C₉)heteroaryl-(CH₂)_(n)— group may contain from one to threeheteroatoms independently selected from nitrogen, sulfur or oxygen,wherein said (C₂-C₉)heteroaryl moiety of said(C₂-C₉)heteroaryl-(CH₂)_(n)— group may optionally be substituted on anyof the ring carbon atoms capable of forming an additional bond(preferably one to three substitutents per ring) with a substituentselected from the group consisting of hydrogen, halo, CN, (C₁-C₆)alkyl,hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O-(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl; (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl—SO₂—, (C₁-C₆)alkyl—SO₂-NH—, H₂N—SO₂—,H₂N—SO₂-(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂-(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂-(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl—SO₃—, phenyl,(C3-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl; and

[1127] wherein said aryl moiety of said R₃ aryl-(CH₂)_(n)— group isoptionally substituted phenyl or naphthyl, wherein said phenyl andnaphthyl may optionally be substituted with from one to threesubstituents independently selected from the group consisting ofhydrogen, halo, CN, (C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O-(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl—SO₂—, (C₁-C₆)alkyl—SO₂-NH—, H₂N—SO₂—,H₂N—SO₂-(C₁-C₆)alkyl, (C₁-C₆)alkyl HN—SO₂-(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂-(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl—SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

[1128] or R₃ and the carbon to which it is attached form a five to sevenmembered carbocyclic ring, wherein any of the carbon atoms of said fivemembered carbocyclic ring may optionally be substituted with asubstituent selected from the group consisting of hydrogen, halo, CN,(C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,HO—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—, (C₁-C₆)alkyl-(C═O)—O-(C₁-C₆)alkyl, H(O═C)—,H(O═C)—(C₁-C₆)alkyl, (C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl,NO₂, amino, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—(NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl—SO₂—, (C₁-C₆)alkyl—SO₂-NH—, H₂N—SO₂—,H₂N—SO₂-(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂-(C₁-C₆)alkyl,f(C₁-C₆)alkyl]₂N—SO₂-(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl—SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;wherein one of the carbon-carbon bonds of said five to seven memberedcarbocyclic ring may optionally be fused to an optionally substitutedphenyl ring, wherein said substitutents may be independently selectedfrom hydrogen, halo, CN, (C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O-(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)aikyl—SO₂—, (C₁-C₆)alkyl—SO₂-NH—, H₂N—SO₂—,H₂N—SO₂-(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂-(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂-(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl—SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

[1129] wherein R₄ is hydrogen, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C═O)—, (C₃-C₁₀)cycloalkyl-(CH₂)_(q)—,(C₂-C₉)heterocycloalkyl-(CH₂)_(q)—, (C₂-C₉)heteroaryl-(CH₂)_(q)—,phenyl-(CH₂)_(q)—, or naphthyl-(CH₂)_(q)—; wherein said(C₂-C₉)heterocycloalkyl, (C₂-C₉)heteroaryl, phenyl and naphthyl groupsmay be optionally substituted with one or two substituents from thegroup consisting of hydrogen, halo, cyano, (C₁-C₆)alkyl, hydroxy,hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O-(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl, (C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂ amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino (C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl—SO₂—, (C₁-C₆)alkyl—SO₂-NH—, H₂N—SO₂—,H₂N—SO₂-(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂-(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂-(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl—SO₃, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

[1130] wherein R₅ is hydrogen, (C₁-C₆)alkyl or amino; or

[1131] R₄ and R₅ together with the nitrogen atom to which they areattached form a (C₂-C₉)heterocycloalkyl group optionally substitutedwith one or two substituents selected from the group consisting ofhydrogen, halo, cyano, (C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O-(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl, (C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino (C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl—SO₂—, (C₁-C₆)alkyl—SO₂—NH—, H₂N—SO₂—,H₂N—SO₂-(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂-(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂-(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl—SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

[1132] wherein R⁶ is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy-(CH₂)_(g)—,(C₁-C₆)alkoxy(C═O)—(CH₂)_(g)—, (C₁-C₆)alkyl-(SO₂)—(CH₂)_(g)—,(C₆-C₁₀)aryloxy-(CH₂)_(g)—, (C₆-C₁₀)aryloxy(C═O)—(CH₂)_(g)—, or(C₆-C₁₀)aryl-(SO₂)—(CH₂)_(g)—;

[1133] wherein g is an integer from zero to four;

[1134] wherein m is an integer from zero to four;

[1135] wherein n is an interger from zero to six;

[1136] with the proviso that when one of R⁴ or R⁵ is hydrogen, and theother of R⁴ or R⁵ is (C₁-C₆)alkyl; R² is (C₃-C₁₀)cycloalkyl or isopropyland R³ is (C₃-C₅)alkyl, phenyl, methylvinyl, dimethylvinyl, halovinyl,hydroxy(C₁-C₃)alkyl or amino(C₁-C₄)alkyl then R¹ must be other thanindol-5-yl, 6-azaindol-2-yl, 2,3-dichloro-pyrrol-5-yl,4-hydroxyquinolin-3-yl, 2-hydroxyquinoxalin-3-yl, 6-azaindolin-3-yl, oroptionally substituted indol-2 or 3-yl;

[1137] and the pharmaceutically acceptable salts of such compounds.

[1138] Unless otherwise indicated, the alkyl and alkenyl groups referredto herein, as well as the alkyl moieties of other groups referred toherein (e.g., alkoxy), may be linear or branched, and they may also becyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl) or be linear or branched and contain cyclic moieties. Suchalkyl and alkoxy groups may be substituted with one, two or threehalogen and/or hydroxy atoms, preferably fluorine atoms.

[1139] Unless otherwise indicated, “halogen” includes fluorine,chlorine, bromine, and iodine.

[1140] “(C₃-C₁₀)cycloalkyl” when used herein refers to cycloalkyl groupscontaining zero to two levels of unsaturation such as cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,1,3-cyclohexadiene, cycloheptyl, cycloheptenyl, bicyclo[3.2.1]octane,norbornanyl, and the like. “(C₂-C₉)heterocycloalkyl” when used hereinrefers to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl,methylenedioxyl, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl,isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl,1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl,1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl,tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, chromanyl, andthe like. One of ordinary skill in the art will understand that theconnection of said (C₂-C₉)heterocycloalkyl rings is through a carbon ora sp³ hybridized nitrogen heteroatom.

[1141] “(C₂-C₉)heteroaryl” when used herein refers to furyl, thienyl,thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl,triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl,pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl,6,7-dihydro-5H-[1 ]pyrindinyl, benzo[b]thiophenyl,5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl,quinoxalinyl, quinazolinyl, benzoxazinyl, and the like. One of ordinaryskill in the art will understand that the connection of said(C₂-C₉)heterocycloalkyl rings is through a carbon atom or a sp³hybridized nitrogen heteroatom.

[1142] “Aryl” when used herein refers to phenyl or naphthyl.

[1143] “Protected amine” and “protected amino” refers to an amine groupwith one of the hydrogen atoms replaced with a protecting group (P). Anysuitable protecting group may be used for amine protection. Suitableprotecting groups include carbobenzyloxy, t-butoxy carbonyl (BOC) or9-fluorenyl-methylenoxy carbonyl.

[1144] Compounds of Formula CCR1-l and their methods of manufacture aredisclosed in commonly assigned U.S. patent application Ser. No.09/380,269, filed Feb. 5, 1998, U.S. patent application Ser. No.09/403,218, filed Jan. 18, 1999, PCT Publication No. WO98/38167, and PCTPublication No. WO99/40061, all of which are incorporated herein byreference in their entireties for all purposes.

[1145] In a preferred embodiment, the CCR1 inhibitor is selected fromone of the following compounds of Formula CCR1-l:

[1146] quinoxaline-2-carboxylic acid 4(R)-carbamoyl-1(S)-(3-chloro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;

[1147] 7,8-difluoro-quinoline-3-carboxylic acid(1S)-benzyl-4(R)-carbamoyl-2(S),7-dihydroxy-7-methyl-octyl)-amide;

[1148] 6,7,8-trifluoro-quinoline-3-carboxylic acid(1(S)-benzyl-4(R)-carbamoyl-2(S),7-dihydroxy-7-methyl-octyl)-amide;

[1149] quinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-(3-fluoro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;

[1150] quinoxaline-2-carboxylic acid(1(S)-benzyl-2(S),7-dihydroxy-4(R)-hydroxycarbamoyl-7-methyl-octyl)-amide;

[1151] quinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-(2-chloro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;

[1152] quinoxaline-2-carboxylic acid[1(S)-(2-fluoro-benzyl)-2(S),7-dihydroxy-4(R)-hydroxycarbamoyl-7-methyl-octyl]-amide;

[1153] quinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-(2-fluoro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;

[1154] quinoxaline-2-carboxylic acid[1(S)-(3,4-difluoro-benzyl)-2(S),7-dihydroxy-4(R)-hydroxycarbamoyl-7-methyl-octyl]-amide;

[1155] quinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-(3,4-difluoro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;

[1156] quinoxaline-2-carboxylic acid(4(R)-carbamoyl-2(S),7-dihydroxy-7-methyl-1(S)-naphthalen-1-ylmethyl-octyl)-amide;

[1157] 7,8-difluoro-quinoline-3-carboxylic acid1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide;

[1158] 8-fluoro-quinoline-3-carboxylic acid1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide;

[1159] quinoxaline-2-carboxylic acid[4(R)-carbamoyl-7-fluoro-1-(3(S)-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide;

[1160] quinoxaline-2-carboxylic acid[4(R)-carbamoyl-1-(2(S)-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide;

[1161] quinoxaline-2-carboxylic acid[1(S)-benzyl-4(S)-carbamoyl-4(S)-(2,6-dimethyl-tetrahydro-pyran-4-yl)-2(S)-hydroxy-butyl]-amide;

[1162] quinoxaline-2-carboxylic acid1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide;

[1163] quinoxaline-2-carboxylic acid1(S)-benzyl-5-cyclohexyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)-amide;

[1164] quinoxaline-2-carboxylic acid1(S)-cyclohexylmethyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide;

[1165] quinoxaline-2-carboxylic acid [1(S)-benzyl-2(S)-hydroxy-4(S)-10hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide;

[1166] quinoxaline-2-carboxylic acid[1(S)-benzyl-4(S)-(4,4-difluoro-1-hydroxy-cyclohexyl)-2(S)-hydroxy-4-hydroxycarbamoyl-butyl]-amide;

[1167] quinoxaline-2-carboxylic acid[1(S)-benzyl-4(S)-carbamoyl-4(S)-(4,4-difluoro-cyclohexyl)-2(S)-hydroxy-butyl]-amide;

[1168] quinoline-3-carboxylic acid(1(S)-benzyl-4(S)-carbamoyl-4-cyclohexyl-2(S)-hydroxy-butyl)-amide;

[1169] quinoxaline-2-carboxylic acid(4(R)-carbamoyl-2(S)-hydroxy-7-methyl-1(S)-thiophen-2-ylmethyl-octyl)-amide;

[1170] quinoxaline-2-carboxylic acid1(S)-benzyl-4(R)-carbamoyl-7-chloro-2(S)-hydroxy-oct-6-enyl)-amide;

[1171] quinoxaline-2-carboxylic acid1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-phenyl-pentyl)-amide;

[1172]N-1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-5,6-dichloro-nicotinamide;

[1173] quinoxaline-2-carboxylic acid(4(R)-carbamoyl-2(S)-hydroxy-7-methyl-1(S)-thiazol-4(R)-ylmethyl-octyl)-amide;

[1174] benzothiazole-2-carboxylic acid1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide;and

[1175] benzofuran-2-carboxylic acid1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide.

[1176] In another preferred embodiment, the CCR1 compound has a formulaIa-1:

[1177] wherein the substituents are as defined above.

[1178] In a preferred method of making the compound Ia-1, the reactionis started with Scheme 1. In the herein described processes, thesubstituents are as defined for CCR1-I, and the following:

[1179] R₇ is hydroxy, (C₁-C₆)alkyl, or phenyl wherein the phenyl groupunsubstituted or substituted with one, two, or three (C₁-C₆)alkyl,hydroxy, or halogen groups;

[1180] R₈ is hydroxy or halogen;

[1181] R₉ is phenyl, naphthyl, (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl or(C₂-C₉)heteroaryl, wherein each of said phenyl, naphthyl,(C₃-C₁₀)cycloalkyl or (C₂-C₉)heteroaryl groups may be unsubstituted orsubstituted with one, two, or three substituents independently selectedfrom the group consisting of halogen, cyano, and (C₁-C₆)alkyl;

[1182] P is a protecting group;

[1183] X is hydroxy or halogen; and

[1184] q is 0, 1, 2, 3, or 4.

[1185] In scheme 1 step 1, a compound of the formula (VI-1) is reducedwith a reducing agent under heat to form a compound of the formula(VId-1). In one embodiment, the reducing agent is aluminumtriisopropoxide and isopropanol. Preferably, the temperature ismaintained above room temperature, more preferably between about 60° C.and about 82° C. The product alcohol can be isolated by either coolingthe reaction mixture to room temperature, diluting with more isopropanoland collecting the crystalline material or by cooling the reaction toroom temperature and adding 1N HCL and water and collecting thecrystalline material.

[1186] Step 2 of scheme 1 includes reacting a compound of the formulaR₇—SO₂—X and a compound of the formula (VId-1) in the presence of a baseto form the compound of the formula (VIe-1). Any amine base is suitable,including pyridine, triethylamine, N-methylmayholine, anddiisoyropylethylamine. In one embodiment, R₇—SO2—R₈ is p-toluenesulfonicacid, methanesulfonic acid, sulfuric acid, or methanesulfonyl chloride.In another embodiment, the conversion of hydroxy dioxane (VId-1) todioxane oxazolidinone (VIe-1) can be achieved by treatment of thehydroxy dioxane (VId-1) with methanesulfonyl chloride and triethylaminein tetrahydrofuran solution and heating the mixture to cause thecyclization of the mesylate formed in situ to the oxazolidinone.

[1187] In step 3 of scheme 1, a compound of the formula (VIf-1) may beformed by heating the compound of the formula (VIe-1). The reaction mayproceed by dissolving compound VIe-1 in a solvent such as pyridine orN-methyl imidazole and heating the mixture for several hours attemperature from about 50° C. to about 100° C.; preferably at about 80°C. The mesylate (VIf-1) may be recovered by extraction into an organicsolvent such as ethyl acetate and removal of the amine solvents byextraction of the solution with aqueous acid.

[1188] Step 4 of scheme 1 depicts reacting hydroxylamine hydrochloride,a compound of the formula R₇—SO₂—X, and a compound of the formula(VIf-1) to form a compound of the formula (VIg-1). In one embodiment,R₇—SO2—X is p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid,or methanesulfonyl chloride. The reaction may occur in a solvent, suchas methanol. In one embodiment, the reaction occurs in methanol withtosic acid at reflux for 8 to 24 hours. The resulting nitrileoxazolidinone contains a small amount of the corresponding ethyl esterwhich is not removed since it also is converted to the desired lactonein subsequent steps.

[1189] Step 5 of scheme 1 includes a) hydrolyzing a compound of theformula (VIg-1) with an aqueous solution in the presence of a base, b)protecting the amine group of the compound so formed, and c) cyclizingthe compound so formed with heat and an acid catalyst. In oneembodiment, the compound VIg-1 is hydrolyzed with sodium hydroxide. ThepH is adjusted to approximately 10 and tetrahydrofuran and BOCdicarbonate are added. This provides the protected hydroxy acid, whichmay be heated in 10% acetic acid and toluene to provide the protectedamine lactone (V-1).

[1190] The compound of formula (V-1) may also be produced according toscheme 2.

[1191] In step 1 of scheme 2, a compound of the formula (VI-1) may bereacted with ozone to for a compound of the formula (VIa-1). Thecompound VI-1 may be present in a solvent, such as ethyl acetate, andthe ozone introduced through sparging at a temperature below roomtemperature, preferably at about −15° C., until the starting dioxaneketone is substantially reacted. Any excess ozone may be removed bybubbling nitrogen through the solution. The resulting crude ketone estermixture may be isolated after treatment with aqueous sodium bisulfite toremove any hydroperoxides.

[1192] Alternatively, in step 1 of scheme 2, the compound of the formula(VIa-1) may be formed by reacting hypochlorous acid and a compound ofthe formula (VI-1). Such an oxidation reaction typically produceschlorinated forms of the compound VIa-1 as side products in addition othe compound VIa-1. This oxidation reaction proceeds by mixing thecompound VI-1 in solvent, such as acetic acid and/or acetone, and addingsodium hypochlorite, while keeping the mixture at a low temperature,preferably at or below about 0° C.

[1193] As a means to convert the side product chlorinated forms of thecompound VIa-1 to compounds of the formula V-1, the compounds formedfrom the hypochlorous acid oxidation reaction may optionally behydrogenated by reaction with hydrogen in the presence of a catalyst.The hydrogenation may include introducing the products from thehypochlorous acid oxidation reaction into a solvent system oftetrahydrofuran and water, followed by addition of a Pd/C catalyst. Theresulting mixture is subjected to hydrogen above atmospheric pressureand temperature. In one embodiment, the pressure is about 80 pounds persquare inch and the temperature is maintained from about 60° C. to about70° C. until the reaction is substantially complete.

[1194] In step 2 of scheme 2, the compound of the formula (VIb-1) may beformed by reacting a silyating agent and a compound of the formula(VIa-1) and reacting the compound so formed with a reducing agent. Inone embodiment, the reducing agent is N-selectride. In anotheremodiment, the silyating agent is 1,1,1,3,3,3-hexamethyl-disilazane. Thereduction reaction may occur at temperatures below about 0° C.,preferably below about −20° C., more preferably below about −50° C. Inaddition, the reducing agent may be present in slight excess.

[1195] In step 3 of scheme 2, the compound of the formula (V-1) isformed by heating a compound of the formula (VIb-1) in the presence ofan acid catalyst, such as acetic acid. In one embodiment, thecyclization reaction occurs by introducing the compound VIb-1 into asolvent mixture, such as toluene and 10% acetic acid, at the solventreflux temperature for 8 to 16 hours. This provides the desired lactoneas a crystalline solid after work up.

[1196] One method of making the compound of the formula (VI-1) is byreacting a compound of the formula (VII-1)

[1197] with a Grinard reagent formed in situ by addition of2-(2-bromo-ethyl)-[1,3]dioxane to a mixture comprising magnesium and thecompound of the formula (VII-1). In one embodiment, the mixture furthercomprises methyl magnesium chloride and/or methyl magnesium bromide in asolvent. Any exotherm formed from the reaction may be controlled by therate of addition of the bromide.

[1198] The compound of the formula (VII-1) may be formed by couplingN,O-dimethylhydroxylamine hydrochloride and a compound of the formula(VIII-1)

[1199] This coupling reaction may be performed by mixed anhydrideprocedure. In one mixed anhydride procedure, compound VIII-1 is combinedwith methylene chloride and N-methylmorpholine is added followed byisobutyl chloroformate. In a separate mixture, a slurry ofN,O-dimethylhydroxylamine hydrochloride is treated withN-methylmorpholine. The two reaction mixtures are combined and thenquenched with a solution of citric acid in water. This procedurepreferably operates at a temperature below about 20° C., more preferablybelow about 0° C.

[1200] Compounds of formula (V-1) may be used to produce compounds ofthe formula (IVa1-1) according to scheme 3:

[1201] In step 1 of scheme 3, the compound of the formula (IVa1-1) maybe formed by reacting 4-halo-2-methyl-2-butene and a compound of theformula (V-1) in the presence of a base. Exemplary bases include lithiumdialkyl amides such as lithium N-isopropyl-N-cyclohexylamide, lithiumbis(trimethylsilyl)amide, lithium di-isopropylamide, and potassiumhydride. Suitable solvents include aprotic polar solvents such as ethers(such as tetrahydrofuran, glyme or dioxane), benzene, or toluene,preferably tetrahydrofuran. The aforesaid reaction is conducted at atemperature from about −78° C. to about 0° C., preferably at about −78°C. In one embodiment, alkylation of the lactone (V-1) is accomplished byreacting the lactone (V-1) with lithium bis(trimethylsilyl)amide anddimethylallyl bromide in tetrahydrofuran at a temperature from about−78° C. to about −50° C. Reaction times range from several hours or ifan additive such as dimethyl imidazolidinone is present, the reactionmay be complete in minutes.

[1202] Compounds of formula (IVa1-1) may be used to produce compounds ofthe formula (Ia-1) according to scheme 4:

[1203] In step 1 of scheme 4, a compound of the formula (IIIa1-1) isformed by reacting a compound of the formula (IVa1-1) with phosphoricacid. Preferably, this reaction occurs in any suitable solvent, such asnon-alcoholic solvents. Two preferred solvents include tetrahydrofuranand dichloroethane. The reaction may take place at any suitabletemperature, preferably from about −25° C. to about 120° C., morepreferably from about 15° C. to about 40° C. Reaction time is dependenton temperature and batch size, amount other factors, but typicallyreaction time is from about 2 hours to about 14 hours.

[1204] Step 2 of scheme 4 depicts coupling a compound IIIa1-1 with acompound having the formula R₁—CO—X to form a compound having theformula (IIa1-1). This coupling reaction is generally conducted at atemperature from about −30° C. to about 80° C., preferably from about 0°C. to about 25° C. The coupling reaction may occur with a couplingreagent that activates the acid functionality. Exemplary couplingreagents include dicyclohexylcarbodiimide/hydroxybenzotriazole(DCC/HBT), N-3-dimethylaminopropyl-N′-ethylcarbodiimide (EDC/HBT),2-ethyoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), carbonyldiimidazole (CDI), and diethylphosphorylcyanide. The coupling isconducted in an inert solvent, preferably an aprotic solvent, such astetrahydrofuran, acetonitirile, dichloromethane, chloroform, orN,N-dimethylformamide. One preferred solvent is tetrahydrofuran. In oneembodiment, quinoxaline acid is combined with CDI in anhydroustetrahydrofuran and heated to provide the acyl imidazole. CompoundIIIa1-1 is added to the acyl imidazole at room temperature to form thecompound lIa1-1.

[1205] Step 3 of scheme 4 includes reacting the compound of formulaIIa1-1 with an amine having a formula NHR₄R₅to form a compound of theformula (Ia-1). In one embodiment, the amine is ammonia either anhydrousin an organic solvent or as an aqueous solution of ammonium hydroxideadded to a polar solvent at a temperature from about −10° C. to about35° C., preferably at about 30° C. Suitable solvents include, alcohols,such as methanol, ethanol, or butanols; ethers such as tetrahydrofuran,glyme or dioxane; or a mixture thereof, including aqueous mixtures.Preferably the solvent is methanol. In one embodiment, the compoundIIa1-1 is dissolved in methanol which has been saturated with ammoniagas. In another embodiment, the compound IIa1-1 in methanol is treatedwith ammonium hydroxide in tetrahydrofuran at room temperature.

[1206] Scheme 5 represents an alternative method to form compounds offormula Ia-1 from compounds of formula IVa1-1.

[1207] In step 1 of scheme 5, a compound of the formula (IVa1-1) isreacted with a compound of the formula R₉—SO₂—X to form a compound ofthe formula (IVa2-1). Any suitable acidic deprotection reaction may beperformed. In one example, an excess of p-toluenesulfonic acid hydratein ethyl acetate is introduced to the compound IVa1-1 at roomtemperature. Suitable solvents include ethyl acetate, alcohols,tetrahydrofuran, and mixtures thereof. The reaction may proceed atambient or elevated temperatures. Typically, the reaction issubstantially complete within two and twelve hours. The resultingcompound IVa2-1 may be crystallized and separated from the reactionmixture, and may be further purified to remove impurities byrecrystallization from hot ethyl acetate.

[1208] In step 2 of scheme 5, the compound IVa2-1 may be coupled with acompound having the formula R₁—CO—X to form a compound of the formula(IIIa2-1). This coupling reaction is generally conducted at atemperature from about −30° C. to about 80° C., preferably from about 0°C. to about 25° C. The coupling reaction may occur with a couplingreagent that activates the acid functionality. Exemplary couplingreagents include dicyclohexylcarbodiimide/hydroxybenzotriazole(DCC/HBT), N-3-dimethylaminopropyl-N′-ethylcarbodiimide (EDC/HBT),2-ethyoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), carbonyldiimidazole (CDI)/dimethylaminopyridine (DMAP), anddiethylphosphorylcyanide. The coupling is conducted in an inert solvent,preferably an aprotic solvent, such as acetonitirile, dichloromethane,chloroform, or N,N-dimethylformamide. One preferred solvent is methylenechloride. In one embodiment, quinoxaline acid is combined with methylenechloride, oxalyl chloride and a catalytic amount ofN,N-dimethylformamide to form an acid chloride complex. The compoundIVa2-1 is added to the acid chloride complex followed by triethylamineat a temperature from about 0° C. to about 25° C. to form the compoundIIIa2-1.

[1209] Step 3 of scheme 5 includes reacting a compound IIIa2-1 withtrifluoroacetic acid to produce a compound of the formula (IIa2-1). Inone embodiment, the hydration with trifluoroacetic acid occurs inmethylene chloride solution at room temperature. The hydration may takeseveral hours to complete at room temperature. A catalytic amount ofsulfuric acid can be added to the reaction solution to increase the rateof reaction.

[1210] Step 4 of scheme 5 includes reacting the compound of formulaIIa2-1 with an amine having a formula NHR₄R₅ to form a compound of theformula (Ia-1). In one embodiment, the amine is ammonia either anhydrousin an organic solvent or as an aqueous solution of ammonium hydroxideadded to a polar solvent at a temperature from about −10° C. to about35° C., preferably at about 30° C. Suitable solvents include, alcohols,such as methanol, ethanol, or butanols; ethers such as tetrahydrofuran,glyme or dioxane; or a mixture thereof, including aqueous mixtures.Preferably the solvent is methanol. In one embodiment, the compoundIIa2-1 is dissolved in methanol which has been saturated with ammoniagas. In another embodiment, the compound IIa2-1 in methanol is treatedwith ammonium hydroxide in tetrahydrofuran at room temperature.

Solid Drug-Containing Dispersion

[1211] The drug is present in the composition in a solid drug/matrixdispersion comprising a low-solubility drug and a matrix. At least amajor portion of the drug in the dispersion is amorphous. The term “amajor portion” of the drug means that at least 60% of the drug is inamorphous form, rather than a crystalline form. Preferably, the drug inthe dispersion is substantially amorphous. As used herein,“substantially amorphous” means that the amount of the drug in amorphousform is at least 80%. More preferably, the drug in the dispersion is“almost completely amorphous” meaning that the amount of drug in theamorphous form is at least 90% as measured by powder X-ray diffractionor differential scanning

[1212] calorimetry (“DSC”), or any other standard quantitativemeasurement.

[1213] The amorphous drug may exist in the drug/matrix dispersion as asolid solution of drug homogeneously distributed throughout thedispersion, or a portion of the drug may exist in relatively drug-richdomains. Preferably, the solid dispersion is substantially homogeneousso that the amorphous drug is dispersed as homogeneously as possiblethroughout the dispersion. As used herein, “substantially homogeneous”means that the amount of the drug present in drug-rich amorphous domainswithin the dispersion is less than 20%. Preferably, the dispersion is“completely homogeneous,” meaning that the amount of drug in drug-richdomains is less than 10%.

[1214] While the dispersion may have some drug-rich domains, it ispreferred that the dispersion itself have a single glass-transitiontemperature (T_(g)). Alternatively, the T_(g) of the dispersion is atleast 3° C. greater than the T_(g) of the drug alone. This contrastswith a simple physical mixture of amorphous drug particles and matrixparticles which, when the matrix is amorphous, generally displays twodistinct T_(g)s, one that of the drug and one that of the matrix. Whenthe matrix is not amorphous or does not have a T_(g), the T_(g) of thesimple physical mixture generally has the same T_(g) of pure amorphousdrug particles alone. T_(g) as used herein is the characteristictemperature where a glassy material, upon gradual heating, undergoes arelatively rapid (e.g., 10 to 100 seconds) physical change from a glassstate to a rubber state. The T_(g) of the dispersion may be measured bydifferential scanning calorimetry (“DSC”), or any other standardquantitative measurement. Dispersions of the present invention that aresubstantially homogeneous generally are more physically and chemicallystable and, when mixed with concentration-enhancing polymers, haveimproved concentration-enhancing properties, and in turn improvedbioavailability, relative to nonhomogeneous dispersions.

[1215] The solid dispersion also includes one or more components inaddition to the drug, which are collectively referred to as the“matrix.” The matrix is selected such that the dispersion provideseither improved physical stability, improved chemical stability,improved concentration-enhancement, or any combination of these or allthree for the drug as compared to undispersed amorphous drug alone. By“undispersed drug” is meant drug that is not dispersed in the matrix.The matrix may comprise a single component or it may be a mixture of twoor more components. The components may be intimately mixed to form asingle phase or molecular dispersion or they may exist as two or moredistinct phases with differing compositions.

[1216] At least a portion of the matrix is either water swellable,dispersible, or soluble in aqueous solution at physiologically relevantpH (e.g., pH 1-8). The matrix as a whole should be a solid at roomtemperature, and remain substantially solid up to a temperature of atleast about 40° C., preferably up to a temperature of at least about 60°C., and more preferably up to a temperature of at least about 70° C. Inorder to achieve this, the matrix should be comprised of at least one ormore components with a melting point above about 40° C., preferablyabove about 60° C., and more preferably above about 70° C.

[1217] The amount of matrix relative to the amount of drug present inthe dispersion of the present invention depends on the drug and matrixand may vary widely from a drug-to-matrix weight ratio of from 0.01 toabout 4 (e.g., 1 wt % drug to 80 wt % drug). This will vary dependent onthe dose of the drug. When the dose is low, less than about 50 mg, thedrug-to-matrix weight ratio can be quite small, even less than 0.01. Ingeneral, when the dose is relatively high, that is greater than about 50mg, the drug-to-matrix ratio may be as high as 4.

[1218] The components used in the matrix may be polymeric ornon-polymeric, and may comprise a mixture of several components. Thusthe matrix may comprise a mixture of polymeric components, a mixture ofnon-polymeric components, or a mixture of polymeric and non-polymericcomponents.

[1219] The term “polymeric” is used conventionally, meaning a compoundthat is made of monomers connected together to form a larger molecule. Apolymeric component generally consists of at least about 20 monomers.Thus, the molecular weight of a polymeric component will generally beabout 2000 daltons or more. Polymeric matrix components generally willresult in dispersions with improved concentration enhancement relativeto non-polymeric matrix components. Exemplary polymeric components foruse as the matrix include polyethylene glycols, polyoxyethylene glycols,polyethylene-propylene glycol copolymers, polyethylene oxides, polyvinylpyrrolidinone (also referred to as polyvinyl pyrrolidone or povidone orPVP), polyvinyl alcohol, polyethylene-vinyl alcohol copolymers,polyvinyl alcohol polyvinyl acetate copolymers, xanthan gum,carrageenan, hydroxypropyl cellulose, hydroxypropyl methyl cellulose,carboxy methyl cellulose, carboxylic acid-functionalizedpolymethacrylates, amine-functionalized polymethacrylates, chitosan,chitin, polydextrose, dextrin and starch. Also included within thisdefinition are high molecular weight proteins such as gelatin andalbumin.

[1220] Examples of polyethylene glycols and polyoxyethylene glycolsinclude the CARBOWAX7 polymers supplied by Union Carbide (Danbury,Conn.) and the LUTROL E® polymers supplied by BASF (Mount Olive, N.J.).Examples of polyethylene oxide include POLOX® supplied by Union Carbide.Examples of polyvinyl pyrrolidinones include the KOLLIDON® polymerssupplied by BASF. Examples of polyvinyl alcohols and polyvinyl alcoholpolyvinyl acetate copolymers include the ELVANOL® polymers supplied byDuPont Industrial Polymers (Wilmington, Del.). Examples ofpolyethylene-vinyl alcohol copolymers include the EVAL® polymerssupplied by EVALCA (Lisle, Ill.). Examples of xanthan gums include theKETROL® polymers supplied by Monsanto Pharmaceutical Ingredients (St.Louis, Mo.). Examples of carrageenans include the GELCAREN® polymerssupplied by FMC (Philadelphia, Pa.). Examples of hydroxypropyl celluloseinclude the KLUCEL® polymers supplied by Aqualon Division of Hercules(Wilmington, Del.). Examples of hydroxypropyl methyl cellulose includethe MethocelJ polymers manufactured by Dow Chemical (Midland, Mich.).Examples of carboxymethyl cellulose include the AKUCEL® polymerssupplied by Robeco Inc. (New York, N.Y.). Examples of carboxylicacid-functionalized polymethacrylates and amine-functionalizedpolymethacrylates include the EUDRAGITS® supplied by Röhm America Inc.(Piscataway, N.J.). Examples of polydextrose include the LITESSE®polymers supplied by Cultor Food Science (Ardsley, N.Y.).

[1221] By “non-polymeric” is meant that the component is not polymeric.Exemplary non-polymeric materials for use as a matrix component include:alcohols, such as stearyl alcohol and cetyl alcohol, organic acids, suchas stearic acid, citric acid, fumaric acid, tartaric acid, and malicacid; organic bases such as glucosamine, N-methylglucamine, tris(hydroxymethyl)amino methane, and dodecylamine; salts such as sodiumchloride, potassium chloride, lithium chloride, calcium chloride,magnesium chloride, sodium sulfate, potassium sulfate, sodium carbonate,and magnesium sulfate; amino acids such as alanine and glycine; sugarssuch as glucose, sucrose, xylitol, fructose, lactose, mannitol,sorbitol, and maltitol; fatty acid esters such as glyceryl (mono- anddi-) stearates, glyceryl (mono- and di-) behenates, triglycerdes,sorbitan monostearate, saccharose monostearate, glyceryl (palmiticstearic) ester, polyoxyethylene sorbitan fatty-acid esters; waxes, suchas microcrystalline wax, paraffin wax, beeswax, synthetic wax, castorwax, and carnauba wax; alkyl sulfates such as sodium lauryl sulfate andmagnesium lauryl sulfate; and phospholipids, such as lecithin.

[1222] Non-polymeric components have several advantages. Such componentsare generally easier to purify relative to polymeric components, thusdecreasing the amount of unwanted impurities that may react with thedrug. Non-polymeric components also tend to have a higher solubility inan environment of use, resulting in faster dissolution of thedrug/matrix dispersion. In addition, use of non-polymeric components mayresult in simpler processes for forming the drug/matrix dispersion. Forexample, in thermal-based processes, non-polymeric components generallyhave sharper melting points, lower melt viscosities, and fastercongealing rates than polymeric components. In solvent-based processes,non-polymeric components are generally more soluble and often result inlower viscosity solutions than polymeric components.

[1223] In addition, where the matrix comprises a blend of non-polymericand polymeric components, it is preferred in some embodiments for thenon-polymeric component to comprise at least 10 wt % of the matrix.Non-polymeric components often have a lower molecular weight compared topolymeric components, and thus often have the ability to increase thesolubility of the drug in the matrix. As discussed below, this tends toimprove the stability of the drug in the matrix. The non-polymericcomponent may comprise even greater amounts of the matrix, from 25 wt %to 50 wt % or more.

[1224] Dispersions of the drug and matrix may be made according to anyknown process which results in a dispersion with the propertiesdescribed previously. Such processes include mechanical, thermal andsolvent processes. Exemplary mechanical processes include milling andextrusion; melt processes include high temperature fusion, solventmodified fusion and melt-congeal processes; and solvent processesinclude non-solvent precipitation, spray coating and spray-drying.Often, processes may form the dispersion by a combination of two or moreprocess types. For example, when an extrusion process is used thedispersion may be operated at an elevated temperature such that bothmechanical (shear) and thermal means (heat) are used to form thedispersion. See, for example, U.S. Pat. Nos. 4,801,460, 5,456,923 and5,939,099 which describe formation of dispersions via extrusionprocesses; U.S. Pat. Nos. 5,340,591 and 4,673,564 which describe formingdispersions by milling processes; and U.S. Pat. No. 5,707,646 and U.S.Pat. No. 4,894,235 which describe the formation of dispersions viamelt/congeal processes, the disclosures of which are incorporated byreference.

[1225] In one embodiment, the dispersion is formed by a thermal process,such as an extrusion process, a fusion process, or a melt-congealprocess. In such cases, the matrix is selected such that it is suitablefor use in the thermal process. Generally, it is desirable to keep theprocessing temperature as low as possible to avoid thermal degradationof the drug. As such, it is preferred that the matrix as a whole becomefluid at a temperature of less than about 200° C., more preferably lessthan about 160° C., and most preferably less than about 120° C. A matrixthat becomes fluid at a higher temperature than this should only be usedwith drugs that are thermally stable at the required processingtemperature.

[1226] Exemplary materials that are suitable for use as a matrixcomponent for thermal processes include: alcohols, such as stearylalcohol and cetyl alcohol, organic acids, such as stearic acid, citricacid, and malic acid; sugars such as glucose, xylitol, sorbitol, andmaltitol; fatty acid esters such as mono-, di-, and tri-glycerides,glyceryl mono-, di-, and tri-stearates, glyceryl mono-, di-, andtri-behenates, sorbitan monostearate, saccharose monostearate, glyceryl(palmitic stearic) ester, polyoxyethylene sorbitan fatty-acid esters;waxes, such as microcrystalline wax, paraffin wax, beeswax, syntheticwax, castor wax, and carnauba wax; alkyl sulfates such as sodium laurylsulfate; and polymers such as polyethylene glycols, polyoxyethyleneglycols, polyethylene-propylene glycol copolymers, poloxamers,polyethylene oxide, polyvinyl pyrrolidinone (also referred to aspolyvinyl pyrrolidone or povidone or PVP), polyvinyl alcohol,polyethylene-vinyl alcohol copolymers, polyvinyl alcohol polyvinylacetate copolymers, carboxylic acid-functionalized polymethacrylates,and amine-functionalized polymethacrylates. While specific materialshave been discussed as being suitable for use alone in the dispersionsformed by thermal processing, blends of materials may also be suitable.For example, a water-insoluble matrix component such as microcrystallinewax may be blended with a highly water soluble matrix component, such asa poloxamer, to form a water-dispersible matrix.

[1227] The matrix may include a plasticizer as one component of thematrix to reduce processing temperature. Exemplary plasticizers includemineral oils, petrolatum, lanolin alcohols, polyethylene glycol,polypropylene glycol, sorbitol, triethanol amine, benzyl benzoate,dibutyl sebacate, diethyl phthalate, glyceryl monostearate, triacetin,and triethyl citrate. The amount of plasticizer used will depend on themelting point of the other matrix components and the desired processingtemperature. Typically, the ratio of plasticizer to matrix will be 0.01to 0.5, more typically 0.05 to 0.1. Solvents or swelling agents, such aswater, alcohols, ketones, and the like may also be used to reduceprocessing temperature and improve the processability of thecomposition.

[1228] One preferred thermal process is an extrusion process. Here, thelow-solubility drug and the one or more matrix components may be dryblended, with or without the addition of a plasticizer, and the blendfed to a twin-screw extrusion device. The low-solubility drug may besubstantially amorphous prior to forming the blend, but this is not arequirement for the process. The twin-screw extrusion device is designedsuch that there is sufficient heat and mechanical energy (e.g., shear)to form a dispersion, without degradation of the drug or matrix. Theprocessing temperature may vary from about 50° C. up to about 200° C.,depending on the melting point of the drug and the matrix materials.Generally, the higher the melting point of the drug and the matrixcomponents, the higher the processing temperature.

[1229] When the drug has a high solubility in the matrix, a lower amountof mechanical energy will be required to form the dispersion. In suchcases, the processing temperature may be below the melting temperatureof the undispersed amorphous drug but greater than the melting point ofat least a portion of the matrix materials, since the drug will dissolveinto the molten matrix.

[1230] When the drug has a low-solubility in the matrix, a higher amountof mechanical energy may be required to form the dispersion. Here, theprocessing temperature may need to be above the melting point of thedrug and at least some of the matrix components. A high amount ofmechanical energy may be needed to mix the molten drug with the matrixcomponents to form a dispersion. Typically, the lowest processingtemperature and an extruder design that imparts the lowest amount ofmechanical energy (e.g., shear) that produce a satisfactory dispersionis chosen in order to minimize the exposure of drug to harsh conditions.

[1231] Another preferred method for forming dispersions is “solventprocessing,” which consists of dissolution of at least a portion of thedrug and at least a portion of the one or more matrix components in acommon solvent. The term “solvent” is used broadly and includes mixturesof solvents. “Common” here means that the solvent, which can be amixture of compounds, will simultaneously dissolve at least a portion ofthe drug and the matrix material(s).

[1232] Exemplary materials that are suitable for use as a matrixcomponent for solvent processing include alcohols, such as stearylalcohol and cetyl alcohol, organic acids, such as stearic acid, citricacid, fumaric acid, tartaric acid, and malic acid; salts such as sodiumchloride, potassium chloride, lithium chloride, calcium chloride,magnesium chloride, sodium sulfate, potassium sulfate, sodium carbonate,and magnesium sulfate; amino acids such as alanine and glycine; sugarssuch as glucose, sucrose, xylitol, fructose, lactose, mannitol,sorbitol, and maltitol; fatty acid esters such as glyceryl (mono- anddi-) stearates, triglycerides, sorbitan monostearate, saccharosemonostearate, glyceryl (palmitic stearic) ester, polyoxyethylenesorbitan fatty-acid esters; waxes, such as microcrystalline wax,paraffin wax, beeswax, synthetic wax, castor wax, and carnauba wax;alkyl sulfates such as sodium lauryl sulfate and magnesium laurylsulfate; phospholipids, such as lecithin; proteins, such as gelatin andalbumin; and polymers such as polyethylene glycols, polyoxyethyleneglycols, polyethylene-propylene glycol copolymers, polyethylene oxides,polyvinyl pyrrolidinone (also referred to as polyvinyl pyrrolidone orpovidone or PVP), polyvinyl alcohol, polyethylene-vinyl alcoholcopolymers, polyvinyl alcohol polyvinyl acetate copolymers, xanthan gum,carrageenan, hydroxypropyl cellulose, hydroxypropyl methyl cellulose,carboxy methyl cellulose, carboxylic acid-functionalizedpolymethacrylates, amine-functionalized polymethacrylates, chitosan,chitin, polydextrose, and dextrin. While specific materials have beendiscussed as being suitable for use alone in the dispersions formed bysolvent processing, blends of materials may also be suitable.

[1233] After at least a portion of each of the drug and matrix have beendissolved, the solvent is removed by evaporation or by mixing with anon-solvent. Exemplary processes are spray-drying, spray-coating(pan-coating, fluidized bed coating, etc.), and precipitation by rapidmixing of the drug and matrix solution with CO₂, hexane, heptane, waterof appropriate pH, or some other non-solvent. Preferably, removal of thesolvent results in a solid dispersion which is substantiallyhomogeneous. To achieve this end, it is generally desirable to rapidlyremove the solvent from the solution such as in a process where thesolution is atomized and the drug and matrix rapidly solidify.

[1234] In one embodiment, the solvent is removed through the process ofspray-drying. The term spray-drying is used conventionally and broadlyrefers to processes involving breaking up liquid mixtures into smalldroplets (atomization) and rapidly removing solvent from the mixture ina container (spray-drying apparatus) where there is a strong drivingforce for evaporation of solvent from the droplets. The strong drivingforce for solvent evaporation is generally provided by maintaining thepartial pressure of solvent in the spray-drying apparatus well below thevapor pressure of the solvent at the temperature of the drying droplets.This is accomplished by either (1) maintaining the pressure in thespray-drying apparatus at a partial vacuum (e.g., 0.01 to 0.50 atm); (2)mixing the liquid droplets with a warm drying gas; or (3) both. Inaddition, at least a portion of the heat required for evaporation ofsolvent may be provided by heating the spray solution.

[1235] Solvents suitable for spray-drying can be water or any organiccompound in which at least a portion of the drug and matrix are mutuallysoluble. Preferably, the solvent is also volatile with a boiling pointof about 150° C. or less. In addition, the solvent should haverelatively low toxicity and be removed from the dispersion to a levelthat is acceptable according to The International Committee onHarmonization (ICH) guidelines. Removal of solvent to this level mayrequire a processing step such as tray-drying subsequent to thespray-drying or spray-coating process. Preferred solvents includealcohols such as methanol, ethanol, n-propanol, iso-propanol, andbutanol; ketones such as acetone, methyl ethyl ketone and methyliso-butyl ketone; esters such as ethyl acetate and propylacetate; andvarious other solvents such as acetonitrile, methylene chloride,toluene, and 1,1,1-trichloroethane. Mixtures, particularly mixtures ofan organic solvent such as methanol, ethanol or acetone and water areoften desirable. Lower volatility solvents such as dimethyl acetamide ordimethylsulfoxide can also be used. Mixtures of solvents, such as 50%methanol and 50% acetone, can also be used, as can mixtures with wateras long as at least a portion of the matrix and drug are sufficientlysoluble to make the spray-drying process practicable.

[1236] Generally, the temperature and flow rate of the drying gas ischosen so that the drug/matrix-solution droplets are dry enough by thetime they reach the wall of the apparatus that they are essentiallysolid, and so that they form a fine powder and do not stick to theapparatus wall. The actual length of time to achieve this level ofdryness depends on the size of the droplets. Droplet sizes generallyrange from 1 μm to 500 □m in diameter, with 5 to 100 μm being moretypical. The large surface-to-volume ratio of the droplets and the largedriving force for evaporation of solvent leads to actual drying times ofa few seconds or less, and more typically less than 0.1 second. Thisrapid drying is often critical to the particles maintaining a uniform,homogeneous dispersion instead of separating into drug-rich andmatrix-rich phases. Solidification times should be less than 100seconds, preferably less than a few seconds, and more preferably lessthan 1 second. In general, to achieve this rapid solidification of thedrug/matrix solution, it is preferred that the size of droplets formedduring the spray-drying process are less than about 100 □m in diameter.The resultant solid particles thus formed are generally less than about100 □m in diameter.

[1237] Following solidification, the solid powder typically stays in thespray-drying chamber for about 5 to 60 seconds, further evaporatingsolvent from the solid powder. The final solvent content of the soliddispersion as it exits the dryer should be low, since this reduces themobility of drug molecules in the dispersion, thereby improving itsstability. Generally, the solvent content of the dispersion as it leavesthe spray-drying chamber should be less than 10 wt % and preferably lessthan 2 wt %. In some cases, it may be preferable to spray a solvent or asolution of a stabilizer or other excipient into the spray-dryingchamber to form granules, so long as the dispersion is not adverselyaffected.

[1238] Spray-drying processes and spray-drying equipment are describedgenerally in Perry's Chemical Engineers' Handbook, Sixth Edition (R. H.Perry, D. W. Green, J. O. Maloney, eds.) McGraw-Hill Book Co. 1984,pages 20-54 to 20-57. More details on spray-drying processes andequipment are reviewed by Marshall “Atomization and Spray-Drying,” 50Chem. Eng. Prog. Monogr. Series 2 (1954).

[1239] In addition, the matrix may include optional additionalcomponents, such as surfactants, pH modifiers, disintegrants, binders,lubricants, etc.

Improved Drug Stability

[1240] In one aspect of the invention, the low-solubility drug in thecomposition of drug/matrix dispersion and concentration-enhancingpolymer may improve stability relative to the drug in a controlcomposition. The improved stability may be either physical, chemical, orboth. When evaluating chemical stability, the control composition may beeither the drug in undispersed amorphous form mixed with an equivalentamount of concentration-enhancing polymer, or may be a dispersion of thedrug and concentration-enhancing polymer. When evaluating physicalstability, the control composition is the undispersed amorphous drug.

[1241] In one aspect, the drug in the dispersion has improved physicalstability relative to a control composition. By improved physicalstability is meant that the drug dispersed in the matrix remainsamorphous or noncrystalline, or at least crystallizes more slowly, thanthe control composition. This increased physical stability may arise byforming a dispersion which is either thermodynamically stable orkinetically stable.

[1242] Thermodynamically stable dispersions may be formed by selectingthe matrix and drug/matrix ratio such that at least a major portion ofthe drug is dissolved in the matrix at a particular set of conditions oftemperature and relative humidity. At least a “major portion” means atleast 60 wt % of the drug is dissolved. More preferably at least 80% ofthe drug is dissolved, and even more preferably at least 90% of the drugis dissolved in the matrix. In such cases, the drug/matrix dispersionmay be said to be “thermodynamically stable” (under a particular set ofconditions) and thus the drug remains indefinitely dissolved in thematrix as long as it is stored under the appropriate conditions. Thatis, the free energy of the drug in the drug/matrix dispersion is lessthan the free energy of the drug in the crystalline form. Under suchconditions, the dispersion may be a solid solution of amorphous drug inthe matrix. The solubility of drug in the matrix is a function of thetemperature and water content of the drug/matrix dispersion. Thedrug/matrix dispersion must be stored at an appropriate temperature andrelative humidity for the drug to remain soluble in the matrix. As usedherein, thermodynamically stable drug/matrix dispersions are those whichare thermodynamically stable under conventional storage conditions, thatis, from 25° C. to 50° C. and from 20% to 75% relative humidity.

[1243] For thermodynamically stable drug/matrix dispersions, the matrixcomponent is chosen to complement the physical characteristics of thedrug to result in improved solubility of the drug in the matrix.Comparison of physical properties of the drug and matrix materials, suchas the hydrophilic-lipophilic balance (HLB), solubility parameter, orlogP value, can be used to select suitable matrix components for usewith a specific drug to obtain a thermodynamically stable dispersion.For example, when the drug is relatively hydrophobic, at least a portionof the matrix should be relatively hydrophobic. Exemplary hydrophobicmatrix components include glycerides, fatty acids, and fatty alcohols.If the drug is relatively hydrophilic, preferably at least a portion ofthe matrix should be hydrophilic. Exemplary hydrophilic matrixcomponents include organic acids, short-chain monoglycerides,short-chain fatty acids, sugars, polydextrose, polyvinyl pyrrolidinone(also referred to as polyvinyl pyrrolidone or povidone or PVP),polyethylene oxides, and polyethylene glycols. In general, thedrug/matrix ratio will depend on the particular drug and matrix. Wherethe drug is completely miscible in the matrix, the drug/matrix ratio maybe any value. Where the drug is not completely miscible in the matrix,the concentration of drug in the matrix should be less than thenucleation concentration. This is typically about 1.5- to 3-fold thesolubility of the drug in the matrix. Thus, it is preferred that thematrix is chosen so that the solubility of the drug in the matrix is atleast 30%, and more preferably at least 50%, of the concentration of thedrug in the matrix.

[1244] Alternatively, where the drug content in the dispersion exceedsthe drug solubility in the matrix, the dispersion may nonetheless be“kinetically stable,” even though the dispersion is notthermodynamically stable. By “kinetically stable” is simply meant thateven though the free energy of the drug is lower in the crystalline formthan in the drug/matrix dispersion, the matrix interferes with theability of the drug to crystallize. Kinetic stability may arise from avariety of mechanisms, including (1) simple dilution of the drug in thematrix so that the distance between adjacent drug molecules is increasedrelative to a control composition; (2) reduced mobility such that thediffusion rate of drug in the matrix is less than the diffusion rate ofdrug in a control composition; and (3) interaction of the drug andmatrix such that the nucleation or growth of drug crystals is inhibited.

[1245] Dispersions which are kinetically stable due to dilution may beformed by simply forming a dilute homogeneous dispersion. Thus, theprocessing conditions should be chosen to result in a dispersion that isat least substantially homogeneous, and more preferably completelyhomogeneous. For example, a thermal process may be used in which thedrug is soluble in the matrix at the processing temperature (e.g., in athermal process such as melt-congeal), and then rapidly solidified bycooling. Generally, stability is improved as the drug/matrix ratiodecreases. Preferably, the drug/matrix ratio is 20 or less, and morepreferably is 10 or less.

[1246] Kinetically stable drug/matrix dispersions may also be formed byreducing the mobility of the drug in the dispersion. Drug mobility maybe reduced by selecting the matrix components such that the T_(g) of theresulting drug/matrix dispersion is higher than that of the controlcomposition. Exemplary matrix components having relatively high T_(g)values include hydroxy propyl methyl cellulose, hydroxypropyl cellulose,polyvinyl pyrrolidone, maltodextrin, polydextrose, starch, dextrin, andtrehalose. In general, T_(g) increases with increasing molecular weight.Thus, for example, saccharide oligomers (such as maltodextrin,polydextrose, starch, and dextrin) generally have a higher T_(g) thantri-saccharides (such as trehalose), which in turn are higher thandi-saccharides (such as sucrose and lactose), which in turn are higherthan mono-saccharides (such as glucose).

[1247] When kinetic stability is achieved due to a high T_(g) value, thematrix and drug content of the dispersion should be chosen such that theT_(g) of the resulting dispersion, when equilibrated with humid airhaving a relative humidity of about 50%, is at least 30° C., andpreferably greater than about 50° C. Preferably, a substantiallyhomogeneous dispersion of the drug and matrix is formed. Even morepreferably, the T_(g) of the matrix material should be sufficiently highsuch that the T_(g) of the resulting dispersion is greater than about70° C., more preferably greater than about 75° C., and most preferablygreater than about 100° C.

[1248] Kinetically stable drug/matrix dispersions may also be formed byinhibiting crystallization, either by inhibiting nucleation, crystalgrowth, or both. Generally, to be a crystallization inhibitor, thematrix must result in a strong drug/matrix interaction. The matrix ischosen to have a “complementary” chemical interaction with the drug.Examples of such complementary chemical interactions are given below.Complementary Matrix Drug Property Property Cationic Anionic AnionicCationic Electron donor Electron acceptor Electron acceptor Electrondonor Hydrogen-bonding donor Hydrogen-bonding acceptor Hydrogen-bondingacceptor Hydrogen-bonding donor

[1249] The complementary chemical interaction between drug and matrixlowers the free energy of the drug in the vicinity of the matrix andinhibits the formation of drug-rich areas.

[1250] In other instances, the matrix is chosen such that theinteraction is not chemically complementary but still results in astrong physical drug/matrix interaction. Examples of such physicalinteractions include (1) if the drug is polar, select the matrix to bepolar; and (2) if the drug is hydrophobic, select the matrix to behydrophobic. These physical interactions lower the free energy of thedrug in the matrix.

[1251] Since kinetic stability may be achieved through one or moremechanisms, the matrix may be selected to reduce the rate ofcrystallization of the drug through one or more mechanisms. For example,a matrix may be selected that has a high T_(g) (to reduce mobility),that has a complementary property relative to the drug (to inhibitcrystallization), and is capable of being processed to yield ahomogeneous dispersion having a low drug/matrix ratio (dilution).

[1252] The physical stability of the drug in the matrix may be evaluatedby measuring the rate of change in the physical state of the drug fromamorphous to crystalline in the matrix and comparing the rate to thecorresponding rate of change provided by a control composition. Thecontrol composition is undispersed amorphous drug alone. The rate ofchange may be measured by determining the fraction of drug in thecrystalline state in the matrix or control over time. This may bemeasured by any standard physical measurement, such as X-raydiffraction, DSC, solid state NMR or Scanning Electron Microscope(“SEM”) analysis. Physically stable compositions of the presentinvention will crystallize at a slower rate than a control composition.Preferably, the rate of crystallization of the drug in the drug/matrixdispersion is less than 90%, and more preferably less than 80%, of therate of crystallization of a control composition.

[1253] In another aspect of the invention, the matrix is selected suchthat the drug in the dispersion has improved chemical stability comparedwith a control composition. The control composition may be either thedrug in the undispersed amorphous form (that is, not dispersed in amatrix material) mixed with the concentration-enhancing polymer, or thecontrol may be a dispersion of the drug in concentration-enhancingpolymer. As used herein, “chemical stability” refers to the rate ofchemical degradation of the drug in a typical storage environment. Typesof degradation reactions that can occur include, but are not limited tohydrolysis, lactonization, esterification, oxidation, reduction, ringcyclization, and transesterification. Dispersing the drug in the matrixpreferably results in a reduced rate of degradation of the amorphousdrug in the dispersion relative to at least one, and preferably both, ofthe controls described above.

[1254] In general, drug degradation may be measured using anyconventional method for measuring the purity or potency of drug in apharmaceutical composition. For example, the amount of active drugpresent in a dispersion may be initially measured using high-performanceliquid chromatography (HPLC) or other analytical techniques well knownin the art. Alternatively, the amount of drug initially present may becalculated from the amount of drug present in the dispersionformulation. The potency of the dispersion is then measured afterstorage at controlled temperature and humidity conditions for anappropriate period of time. A decrease in potency indicates that achemical reaction has occurred, leading to a decrease in the amount ofactive drug present in the dispersion, and is an indication of poorchemical stability.

[1255] An alternative method used to evaluate chemical stability is toanalyze the rate of increase in the amount of drug degradant(s) in thedispersion, which would indicate reaction of the drug. An HPLC or otheranalytical technique may be used to determine the concentration of drugdegradant(s) in a dispersion. The amount of the degradant(s) is measuredbefore and after storage under controlled storage conditions. The amountof increase in the drug degradant(s) may be used to determine the amountof decrease in percent “purity of the drug.” The “percent drug purity”is defined as 100 times the total amount of drug present divided by thetotal amount of drug initially present. Thus, percent drug purity may becalculated by the formula${{wt}\quad \% \quad {drug}\quad {purity}} = {\left( \frac{\begin{matrix}{{total}\quad {{amt}.\quad {of}}} \\{{drug}\quad {present}}\end{matrix}}{\begin{matrix}{{total}\quad {{amt}.\quad {of}}} \\{{drug}\quad {{init}.\quad {present}}}\end{matrix}} \right)*100}$

[1256] When the drug purity is calculated from the total amount ofimpurities, “percent drug purity” may be calculated by assuming that the“total amount of drug initially present,” given in wt %, is equal to 100wt % minus the wt % of total initial impurities, and that “total amountof drug present” is equal to 100 wt % minus the wt % of total impuritiesafter storage, that is, at some later time. This method is equivalent tocalculating “percent drug purity” by the formula:${{wt}\quad \% \quad {drug}\quad {purity}} = {\left\lbrack {1 - \left( \frac{\begin{matrix}{{total}\quad {{amt}.\quad {of}}} \\{{impurities}\quad {present}}\end{matrix}}{\begin{matrix}{{total}\quad {{amt}.\quad {of}}} \\{{drug}\quad {{init}.\quad {present}}}\end{matrix}} \right)} \right\rbrack*100}$

[1257] The rate at which drug degradation occurs is generally dependenton the storage conditions. The drug, when formulated as a composition ofthe present invention, should be stable at ambient temperature andhumidity conditions (e.g., relative humidities of 20% to 60%) for longperiods of time, such as months or years. However, to expedite testing,the storage conditions may employ elevated temperature and/or humidityto simulate longer storage times at ambient conditions. The storage timemay vary from a few days to weeks or months, depending on the reactivityof the drug and the storage conditions.

[1258] A “degree of degradation” of drug following storage may bedetermined by subtracting the final drug percent purity (eitherdetermined by measuring the decrease in drug present or an increase inthe amount of drug degradants present) from the initial percent purity.For example, for a dispersion initially containing 100 mg drug, and nomeasurable impurities it would have an initial percent purity of 100 wt%. If, after storage, the amount of drug in the dispersion decreases to95 mg, the final percent purity would be 95 wt % and the “degree ofdegradation” is 5 wt % (100 wt %-95 wt %). Alternatively, if 100 mg ofdrug substance were found to initially have 1 mg of impurities present,it would have an initial “percent purity” of 99 wt %. If, after storage,the total impurities present had increased to 6 wt %, the final percentpurity would be 94 wt % and the “degree of degradation” would be 5 wt %(99 wt %-94 wt %).

[1259] Alternatively, “degree of degradation” can be determined bysubtracting the amount of one or more specific drug degradants initiallypresent from the amount of that specific degradant present afterstorage. Such a measure is useful where there are several drugdegradants, of which only one (or a few) is of concern. The degree ofdegradation may be calculated on the basis of only those degradants thatare of concern, rather than all of the degradants. For example, if adrug initially contained a specific degradant at a concentration of 1 wt% and after storage the concentration of that degradant was 6 wt %, thedegree of degradation would be 5 wt % (6 wt % -1 wt %).

[1260] A relative degree of improvement in chemical stability may bedetermined by taking the ratio of the degree of degradation of the drugin a control composition and the degree of degradation of the drug in atest composition of the present invention under the same storageconditions for the same storage time period. The test composition issimply the drug/matrix dispersion mixed with the concentration-enhancingpolymer. The control composition may be either amorphous drug alonemixed with concentration-enhancing polymer, or may be a dispersion ofthe drug and concentration-enhancing polymer (that is, theconcentration-enhancing polymer replaces the matrix of the dispersion inthe test composition). For example, where the degree of degradation of adrug in a test composition comprised of the drug and matrix is 1 wt %,and the degree of degradation of a control dispersion of drug andconcentration-enhancing polymer is 50 wt %, the relative degree ofimprovement is 50 wt %/1 wt %, or 50. For dispersions of drugs andmatrix of this aspect of the present invention, the relative degree ofimprovement is at least 1.25. When the drug is particularly unstable,larger relative degrees of improvement may be necessary in order for thechemical stability of the dispersion to be pharmaceutically acceptable.In such cases, the invention provides greater chemical stability whenthe relative degree of improvement is at least about 2, preferably atleast about 5, and even more preferably at least 10. In fact, somedispersions may achieve a relative degree of improvement greater than100.

[1261] The particular storage conditions and time of storage may bechosen as convenient depending on the stability of the drug, theparticular concentration-enhancing polymer, and the ratio of drug toconcentration-enhancing polymer. Where the drug is particularlyunstable, or where the dispersion has a low ratio of drug to polymer,then shorter storage time periods may be used. Where the rate of drugdegradation is linear, the relative degree of improvement will beindependent of the storage time. However, where the rate of drugdegradation is non-linear under controlled storage conditions, thestability test used to compare the test composition with the controlcomposition is preferably chosen such that the degree of degradation issufficiently large that it may be accurately measured. Typically, thetime period is chosen so as to observe a degree of degradation of atleast 0.1 wt % to 0.2 wt %. However, the time period is not so long thatthe ratio of drug to polymer changes substantially. Typically, the timeperiod is such that the observed degree of degradation for the testcomposition is less than 50 wt % and preferably less than 20 wt %. Whenthe rate of drug degradation in the control composition is relativelyslow, the test is preferably conducted over a long enough period of timeunder controlled storage conditions to allow a meaningful comparison ofthe stability of the test composition with the control dispersion.

[1262] A stability test which may be used to test whether a compositionmeets the chemical stability criteria described above is storage of thetest composition and the control composition for six months at 40° C.and 75% RH. A relative degree of improvement may become apparent withina shorter time, such as three to five days, and shorter storage timesmay be used for some drugs. When comparing compositions under storageconditions which approximate ambient conditions, e.g., 25° C. and 60%RH, the storage period may need to be from several months up to twoyears.

[1263] In addition, it is preferred that the compositions comprisingdrug and matrix result in drug stability such that the drug has a degreeof degradation of less than about 2 wt %, more preferably less thanabout 0.5 wt %, and most preferably less than about 0.1 wt % when storedat 40° C. and 75% RH for six months, or less than about 2 wt %, morepreferably less than about 0.5 wt %, and more preferably less than about0.1 wt %, when stored at 25° C. and 60% RH for one year, or less thanabout 2 wt %, more preferably less than about 0.5 wt %, and morepreferably less than about 0.1 wt %, when stored at ambient conditionsfor two years. Nevertheless, the compositions of the present inventionmay have a degree of degradation that is much greater than the preferredvalues, so long as the test composition achieves the degree ofimprovement relative to a control composition as described above.

[1264] Dispersing the drug in a suitable matrix can result in improvedchemical stability of the drug by many possible mechanisms. For example,improved chemical stability of the drug may occur by isolating the drugfrom potential reactants, reducing the mobility of the drug, and hence,the rate of reaction of the drug, or both. In such cases the matrixshould be selected such that it preferably does not react with, orcatalyze reactions with the drug or if it does, such a reaction shouldbe acceptably slow. In addition, the matrix should be selected such thatany degradation products of the matrix material itself are not reactivewith the drug. The matrix should also not contain unacceptably highlevels of impurities that could lead to degradation of the drug.

[1265] Many of the matrix materials listed above for formation ofdispersions may be suitable for use in forming chemically stabledispersions, depending on the nature and reactivity of the drug. Thoseskilled in the art will recognize that selection of a matrix forformation of chemically stable dispersions will require selecting thematrix in light of the particular chemical nature of the drug so thatthe dispersion will provide the appropriate chemical stability. Forexample, where the drug is acid-sensitive, the matrix should be eitherneutral or basic.

[1266] The compositions of the present invention are particularly usefulwhere the drug reacts with the concentration-enhancing polymer. Forexample, the present invention may be used where the drug isacid-sensitive and it is desired to use an acidicconcentration-enhancing polymer. Often acidic concentration-enhancingpolymers are preferred because such polymers often result in superioraqueous concentration of the drug in the use environment. However, theacidic polymers may adversely interact with the drug, especially if thedrug is dispersed in the acidic polymer. Accordingly, the presentinvention solves this problem by forming a dispersion with a relativelynon-reactive, neutral matrix to chemically stabilize the drug. Forexample, the acid-sensitive drug may be dispersed in a neutral wax oralcohol or a neutral polymer such as a polyethylene oxide, polyethyleneglycol, or polyvinyl pyrrolidinone (PVP). The dispersion may then bemixed with an acidic concentration-enhancing polymer, resulting in adispersion that has improved chemical stability relative to either asimple physical mixture of the undispersed amorphous drug andconcentration-enhancing polymer or a dispersion of the drug andconcentration-enhancing polymer.

Concentration-Enhancing Polymers

[1267] The composition also includes a concentration-enhancing polymer.By “concentration-enhancing” is meant a polymer present in a sufficientamount so that composition provides, at a minimum, either improved AUC,maximum drug concentration, or relative bioavailability relative to acontrol consisting of an equivalent amount of crystalline drug but withno concentration-enhancing polymer. Concentration-enhancing polymerssuitable for use in the various aspects of the present invention shouldbe pharmaceutically acceptable, and should have at least some solubilityin aqueous solution at physiologically relevant pHs (e.g. 1-8). Almostany neutral or ionizable polymer that has an aqueous-solublitity of atleast 0.1 mg/mL over at least a portion of the pH range of 1-8 may besuitable.

[1268] It is preferred that the concentration-enhancing polymers be“amphiphilic” in nature, meaning that the polymer has hydrophobic andhydrophilic portions. Amphiphilic polymers are preferred because it isbelieved that such polymers tend to have relatively strong interactionswith the drug and may promote the formation of various types ofpolymer/drug assemblies in solution. A particularly preferred class ofamphiphilic polymers are those that are ionizable, the ionizableportions of such polymers, when ionized, constituting at least a portionof the hydrophilic portions of the polymer. For example, while notwishing to be bound by a particular theory, such polymer/drug assembliesmay comprise hydrophobic drug clusters surrounded by theconcentration-enhancing polymer with the polymer=s hydrophobic regionsturned inward towards the drug and the hydrophilic regions of thepolymer turned outward toward the aqueous environment. Alternatively,depending on the specific chemical nature of the drug, the ionizedfunctional groups of the polymer may associate, for example, via ionpairing or hydrogen bonds, with ionic or polar groups of the drug. Inthe case of ionizable polymers, the hydrophilic regions of the polymerwould include the ionized functional groups. In addition, the repulsionof the like charges of the ionized groups of such polymers (where thepolymer is ionizable) may serve to limit the size of the polymer/drugassemblies to the nanometer or submicron scale. Suchdrug/concentration-enhancing polymer assemblies in solution may wellresemble charged polymeric micellar-like structures. In any case,regardless of the mechanism of action, the inventors have observed thatsuch amphiphilic polymers, particularly ionizable cellulosic polymerssuch as those listed below, have been shown to interact with drug so asto maintain a higher concentration of drug in an aqueous useenvironment.

[1269] One class of polymers suitable for use with the present inventioncomprises non-ionizable (neutral) non-cellulosic polymers. Exemplarypolymers include: vinyl polymers and copolymers having at least onesubstituent selected from the group consisting of hydroxyl,alkylacyloxy, and cyclicamido; polyvinyl alcohols that have at least aportion of their repeat units in the unhydrolyzed (vinyl acetate) form;polyvinyl alcohol polyvinyl acetate copolymers; polyvinyl pyrrolidone;and polyethylene polyvinyl alcohol copolymers.

[1270] A preferred class of neutral non-cellulosic polymers arecomprised of vinyl copolymers of at least one hydrophilic,hydroxyl-containing repeat unit and at least one hydrophobic, alkyl- oraryl-containing repeat unit. Such neutral vinyl copolymers are termed“amphiphilic hydroxyl-functional vinyl copolymers.” Amphiphilichydroxyl-functional vinyl copolymers are believed to provide highconcentration enhancements due to the amphiphilicity of these copolymerswhich provide both sufficient hydrophobic groups to interact with thehydrophobic, low-solubility drugs and also sufficient hydrophilic groupsto have sufficient aqueous solubility for good dissolution. Thecopolymeric structure of the amphiphilic hydroxyl-functional vinylcopolymers also allows their hydrophilicity and hydrophobicity to beadjusted to maximize performance with a specific low-solubility drug.

[1271] The preferred copolymers have the general structure:

[1272] wherein A and B represent “hydrophilic, hydroxyl-containing” and“hydrophobic” substituents, respectively, and n and m represent theaverage number of hydrophilic vinyl repeat units and average number ofhydrophobic vinyl repeat units respectively per polymer molecule.Copolymers may be block copolymers, random copolymers or they may havestructures anywhere between these two extremes. The sum of n and m isgenerally from about 50 to about 20,000 and therefore the polymers havemolecular weights from about 2,500 to about 1,000,000 daltons.

[1273] The hydrophilic, hydroxyl-containing repeat units, “A,” maysimply be hydroxyl (—OH) or it may be any short-chain, 1 to 6 carbon,alkyl with one or more hydroxyls attached thereto. Thehydroxyl-substituted alkyl may be attached to the vinyl backbone viacarbon-carbon or ether linkages. Thus, exemplary “A” structures include,in addition to hydroxyl itself, hydroxymethyl, hydroxyethyl,hydroxypropyl, hydroxymethoxy, hydroxyethoxy and hydroxypropoxy.

[1274] The hydrophobic substituent, “B,” may simply be: hydrogen (—H),in which case the hydrophobic repeat unit is ethylene; an alkyl or arylsubstituent with up to 12 carbons attached via a carbon-carbon bond suchas methyl, ethyl or phenyl; an alkyl or aryl substituent with up to 12carbons attached via an ether linkage such as methoxy, ethoxy orphenoxy; an alkyl or aryl substituent with up to 12 carbons attached viaan ester linkage such as acetate, propionate, butyrate or benzoate. Theamphiphilic hydroxyl-functional vinyl copolymers of the presentinvention may be synthesized by any conventional method used to preparesubstituted vinyl copolymers. Some substituted vinyl copolymers such aspolyvinyl alcohol/polyvinyl acetate are well known and commerciallyavailable.

[1275] A particularly convenient subclass of amphiphilichydroxyl-functional vinyl copolymers to synthesize are those where thehydrophobic substituent “B” comprises the hydrophilic substituent “A” towhich an alkylate or arylate group is attached via an ester linkage toone or more of the hydroxyls of A. Such copolymers may be synthesized byfirst forming the homopolymer of the hydrophobic vinyl repeat unithaving the substituent B, followed by hydrolysis of a portion of theester groups to convert a portion of the hydrophobic repeat units tohydrophilic, hydroxyl-containing repeat units having the substituent A.For example, partial hydrolysis of the homopolymer, polyvinylbutyrate,yields the copolymer, vinylalcohol/vinylbutyrate copolymer for which Ais hydroxyl (—OH) and B is butyrate (—OOC—CH₂—CH₂—CH₃).

[1276] For all types of copolymers, the value of n must be sufficientlylarge relative to the value of m that the resulting copolymer is atleast partially water soluble. Although the value of the ratio, n/mvaries depending on the identity of A and B, it is generally at leastabout 1 and more commonly about 2 or more. The ratio n/m can be as highas 200. When the copolymer is formed by hydrolysis of the hydrophobichomopolymer, the relative values of n and m are typically reported in“percent hydrolysis,” which is the fraction (expressed as a percent) ofthe total repeat units of the copolymer that are in the hydrolyzed orhydroxyl form. The percent hydrolysis, H, is given as$H = {100*\left( \frac{n}{n + m} \right)}$

[1277] Thus, vinylbutyrate/vinylalcohol copolymer (formed by hydrolysisof a portion of the butyrate groups) having a percent hydrolysis of 75%has an n/m ratio of 3.

[1278] A particularly preferred family of amphiphilichydroxyl-functional vinyl copolymers are those where A is hydroxyl and Bis acetate. Such copolymers are termed vinylacetate/vinylalcoholcopolymers. Some commercial grades are also sometimes referred to simplyas polyvinylalcohol. However, the true homopolymer, polyvinylalcohol isnot amphiphilic and is almost entirely water insoluble. Preferredvinylacetate/vinylalcohol copolymers are those where H is between about67% and 99.5%, or n/m has a value between about 2 and 200. The preferredaverage molecular weight is between about 2500 and 1,000,000 daltons andmore preferably between about 3000 and about 100,000 daltons.

[1279] Another class of polymers suitable for use with the presentinvention comprises ionizable non-cellulosic polymers. Exemplarypolymers include: carboxylic acid-functionalized vinyl polymers, such asthe carboxylic acid functionalized polymethacrylates and carboxylic acidfunctionalized polyacrylates such as the EUDRAGITS® manufactured by RohmTech Inc., of Maiden, Mass.; amine-functionalized polyacrylates andpolymethacrylates; proteins such as gelatin and albumin; and carboxylicacid functionalized starches such as starch glycolate.

[1280] Non-cellulosic polymers that are amphiphilic are copolymers of arelatively hydrophilic and a relatively hydrophobic monomer. Examplesinclude acrylate and methacrylate copolymers. Exemplary commercialgrades of such copolymers include the EUDRAGITS, which are copolymers ofmethacrylates and acrylates.

[1281] A preferred class of polymers comprises ionizable and neutral (ornon-ionizable) cellulosic polymers with at least one ester- and/orether-linked substituent in which the polymer has a degree ofsubstitution of at least 0.05 for each substituent. It should be notedthat in the polymer nomenclature used herein, ether-linked substituentsare recited prior to “cellulose” as the moiety attached to the ethergroup; for example, “ethylbenzoic acid cellulose” has ethoxybenzoic acidsubstituents. Analogously, ester-linked substituents are recited after“cellulose” as the carboxylate; for example, “cellulose phthalate” hasone carboxylic acid of each phthalate moiety ester-linked to the polymerand the other carboxylic acid unreacted.

[1282] It should also be noted that a polymer name such as “celluloseacetate phthalate” (CAP) refers to any of the family of cellulosicpolymers that have acetate and phthalate groups attached via esterlinkages to a significant fraction of the cellulosic polymer=s hydroxylgroups. Generally, the degree of substitution of each substituent groupcan range from 0.05 to 2.9 as long as the other criteria of the polymerare met. “Degree of substitution” refers to the average number of thethree hydroxyls per saccharide repeat unit on the cellulose chain thathave been substituted. For example, if all of the hydroxyls on thecellulose chain have been phthalate substituted, the phthalate degree ofsubstitution is 3. Also included within each polymer family type arecellulosic polymers that have additional substituents added inrelatively small amounts that do not substantially alter the performanceof the polymer.

[1283] Amphiphilic cellulosics comprise polymers in which the parentcellulosic polymer has been substituted at any or all of the 3 hydroxylgroups present on each saccharide repeat unit with at least onerelatively hydrophobic substituent. Hydrophobic substituents may beessentially any substituent that, if substituted to a high enough levelor degree of substitution, can render the cellulosic polymer essentiallyaqueous insoluble. Examples of hydrophobic substitutents includeether-linked alkyl groups such as methyl, ethyl, propyl, butyl, etc.; orester-linked alkyl groups such as acetate, propionate, butyrate, etc.;and ether- and/or ester-linked aryl groups such as phenyl, benzoate, orphenylate. Hydrophilic regions of the polymer can be either thoseportions that are relatively unsubstituted, since the unsubstitutedhydroxyls are themselves relatively hydrophilic, or those regions thatare substituted with hydrophilic substituents. Hydrophilic substituentsinclude ether- or ester-linked nonionizable groups such as the hydroxyalkyl substituents hydroxyethyl, hydroxypropyl, and the alkyl ethergroups such as ethoxyethoxy or methoxyethoxy. Particularly preferredhydrophilic substituents are those that are ether- or ester-linkedionizable groups such as carboxylic acids, thiocarboxylic acids,substituted phenoxy groups, amines, phosphates or sulfonates.

[1284] One class of cellulosic polymers comprises neutral polymers,meaning that the polymers are substantially non-ionizable in aqueoussolution. Such polymers contain non-ionizable substituents, which may beeither ether-linked or ester-linked. Exemplary ether-linkednon-ionizable substituents include: alkyl groups, such as methyl, ethyl,propyl, butyl, etc.; hydroxy alkyl groups such as hydroxymethyl,hydroxyethyl, hydroxypropyl, etc.; and aryl groups such as phenyl.Exemplary ester-linked non-ionizable substituents include: alkyl groups,such as acetate, propionate, butyrate, etc.; and aryl groups such asphenylate. However, when aryl groups are included, the polymer may needto include a sufficient amount of a hydrophilic substituent so that thepolymer has at least some water solubility at any physiologicallyrelevant pH of from 1 to 8.

[1285] Exemplary non-ionizable cellulosic polymers that may be used asthe polymer include: hydroxypropyl methyl cellulose acetate,hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl methyl cellulose, hydroxyethyl celluloseacetate, and hydroxyethyl ethyl cellulose.

[1286] A preferred set of neutral cellulosic polymers are those that areamphiphilic. Exemplary polymers include hydroxypropyl methyl celluloseand hydroxypropyl cellulose acetate, where cellulosic repeat units thathave relatively high numbers of methyl or acetate substituents relativeto the unsubstituted hydroxyl or hydroxypropyl substituents constitutehydrophobic regions relative to other repeat units on the polymer.

[1287] A preferred class of cellulosic polymers comprises polymers thatare at least partially ionizable at physiologically relevant pH andinclude at least one ionizable substituent, which may be eitherether-linked or ester-linked. Exemplary ether-linked ionizablesubstituents include: carboxylic acids, such as acetic acid, propionicacid, benzoic acid, salicylic acid, alkoxybenzoic acids such asethoxybenzoic acid or propoxybenzoic acid, the various isomers ofalkoxyphthalic acid such as ethoxyphthalic acid and ethoxyisophthalicacid, the various isomers of alkoxynicotinic acid such asethoxynicotinic acid, and the various isomers of picolinic acid such asethoxypicolinic acid, etc.; thiocarboxylic acids, such as thioaceticacid; substituted phenoxy groups, such as hydroxyphenoxy, etc.; amines,such as aminoethoxy, diethylaminoethoxy, trimethylaminoethoxy, etc.;phosphates, such as phosphate ethoxy; and sulfonates, such as sulphonateethoxy. Exemplary ester linked ionizable substituents include:carboxylic acids, such as succinate, citrate, phthalate, terephthalate,isophthalate, trimellitate, and the various isomers ofpyridinedicarboxylic acid, etc.; thiocarboxylic acids, such asthiosuccinate; substituted phenoxy groups, such as amino salicylic acid;amines, such as natural or synthetic amino acids, such as alanine orphenylalanine; phosphates, such as acetyl phosphate; and sulfonates,such as acetyl sulfonate. For aromatic-substituted polymers to also havethe requisite aqueous solubility, it is also desirable that sufficienthydrophilic groups such as hydroxypropyl or carboxylic acid functionalgroups be attached to the polymer to render the polymer aqueous solubleat least at pH values where any ionizable groups are ionized. In somecases, the aromatic substituent may itself be ionizable, such asphthalate or trimellitate substituents.

[1288] Exemplary cellulosic polymers that are at least partially ionizedat physiologically relevant pHs include: hydroxypropyl methyl celluloseacetate succinate, hydroxypropyl methyl cellulose succinate,hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulosesuccinate, hydroxyethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, hydroxyethyl methyl cellulose acetatesuccinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethylcellulose, carboxymethyl cellulose, ethyl carboxymethyl cellulose,cellulose acetate phthalate, methyl cellulose acetate phthalate, ethylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate,hydroxypropyl methyl cellulose acetate phthalate, hydroxypropylcellulose acetate phthalate succinate, hydroxypropyl methyl celluloseacetate succinate phthalate, hydroxypropyl methyl cellulose succinatephthalate, cellulose propionate phthalate, hydroxypropyl cellulosebutyrate phthalate, cellulose acetate trimellitate, methyl celluloseacetate trimellitate, ethyl cellulose acetate trimellitate,hydroxypropyl cellulose acetate trimelli-tate, hydroxypropyl methylcellulose acetate trimelli-tate, hydroxypropyl cellulose acetatetrimellitate succinate, cellulose propionate trimellitate, cellulosebutyrate trimellitate, cellulose acetate terephthalate, celluloseacetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylicacid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate,ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acidcellulose acetate, ethyl phthalic acid cellulose acetate, ethylnicotinic acid cellulose acetate, and ethyl picolinic acid celluloseacetate.

[1289] Exemplary cellulosic polymers that meet the definition ofamphiphilic, having hydrophilic and hydrophobic regions include polymerssuch as cellulose acetate phthalate and cellulose acetate trimellitatewhere the cellulosic repeat units that have one or more acetatesubstituents are hydrophobic relative to those that have no acetatesubstituents or have one or more ionized phthalate or trimellitatesubstituents.

[1290] A particularly desirable subset of cellulosic ionizable polymersare those that possess both a carboxylic acid functional aromaticsubstituent and an alkylate substituent and thus are amphiphilic.Exemplary polymers include cellulose acetate phthalate, methyl celluloseacetate phthalate, ethyl cellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, hydroxylpropyl methyl cellulose phthalate,hydroxypropyl methyl cellulose acetate phthalate, hydroxypropylcellulose acetate phthalate succinate, cellulose propionate phthalate,hydroxypropyl cellulose butyrate phthalate, cellulose acetatetrimellitate, methyl cellulose acetate trimellitate, ethyl celluloseacetate trimellitate, hydroxypropyl cellulose acetate trimellitate,hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate succinate, cellulose propionatetrimellitate, cellulose butyrate trimellitate, cellulose acetateterephthalate, cellulose acetate isophthalate, cellulose acetatepyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropylsalicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate,hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acidcellulose acetate, ethyl nicotinic acid cellulose acetate, and ethylpicolinic acid cellulose acetate.

[1291] Another particularly desirable subset of cellulosic ionizablepolymers are those that possess a non-aromatic carboxylate substituent.Exemplary polymers include hydroxypropyl methyl cellulose acetatesuccinate, hydroxypropyl methyl cellulose succinate, hydroxypropylcellulose acetate succinate, hydroxyethyl methyl cellulose acetatesuccinate, hydroxyethyl methyl cellulose succinate, and hydroxyethylcellulose acetate succinate. Of these. cellulosic polymers that are atleast partially ionized at physiologically relevant pHs, the inventorshave found the following to be most preferred: hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methyl cellulose phthalate,cellulose acetate phthalate and cellulose acetate trimellitate. The mostpreferred is hydroxypropyl methyl cellulose acetate succinate.

[1292] Another preferred class of polymers consists of neutralizedacidic polymers. By “neutralized acidic polymer” is meant any acidicpolymer for which a significant fraction of the “acidic moieties” or“acidic substituents” have been “neutralized”; that is, exist in theirdeprotonated form. By “neutralized acidic cellulosic polymers” is meantany cellulosic “acidic polymer” for which a significant fraction of the“acidic moieties” or “acidic substituents” have been “neutralized.” By“acidic polymer” is meant any polymer that possesses a significantnumber of acidic moieties. In general, a significant number of acidicmoieties would be greater than or equal to about 0.1 milliequivalents ofacidic moieties per gram of polymer. “Acidic moieties” include anyfunctional groups that are sufficiently acidic that, in contact with ordissolved in water, can at least partially donate a hydrogen cation towater and thus increase the hydrogen-ion concentration. This definitionincludes any functional group or “substituent,” as it is termed when thefunctional group is covalently attached to a polymer, that has a pK_(a)of less than about 10. Exemplary classes of functional groups that areincluded in the above description include carboxylic acids,thiocarboxylic acids, phosphates, phenolic groups, and sulfonates. Suchfunctional groups may make up the primary structure of the polymer suchas for polyacrylic acid, but more generally are covalently attached tothe backbone of the parent polymer and thus are termed “substituents.”Neutralized acidic polymers are described in more detail in commonlyassigned provisional patent application U.S. Serial No. 60/300,256entitled “Pharmaceutical Compositions of Drugs and Neutralized AcidicPolymers” filed Jun. 22, 2001, the relevant disclosure of which isincorporated by reference.

[1293] While specific polymers have been discussed as being suitable foruse in the mixtures of the present invention, blends of such polymersmay also be suitable. Thus, the term “concentration-enhancing polymer”is intended to include blends of polymers in addition to a singlespecies of polymer.

Preparation of Compositions

[1294] The compositions of the present invention may be prepared by anymethod that results in a mixture of the drug/matrix dispersion and theconcentration-enhancing polymer. Mixing processes include physicalprocessing as well as wet-granulation and coating processes. Anyconventional mixing method that does not substantially convert thedrug/matrix dispersion and concentration-enhancing polymer into anothermolecular dispersion may be used. The resulting mixture may be a solidcomposition comprising the concentration-enhancing polymer suspended inthe drug/matrix dispersion, a mixture of separate drug/matrix dispersionparticles and concentration-enhancing particles interspersed with oneanother, a series of respective layers of drug/matrix dispersion andconcentration-enhancing polymer, or any other mixture of drug/matrixdispersion and concentration-enhancing polymer.

[1295] For example, mixing methods include convective mixing, shearmixing, or diffusive mixing. Convective mixing involves moving arelatively large mass of material from one part of a powder bed toanother, by means of blades or paddles, revolving screw, or an inversionof the powder bed. Shear mixing occurs when slip planes are formed inthe material to be mixed. Diffusive mixing involves an exchange ofposition by single particles. These mixing processes can be performedusing equipment in batch or continuous mode. Tumbling mixers (e.g.,twin-shell) are commonly used equipment for batch processing. Continuousmixing can be used to improve composition uniformity. Continuous mixersinclude “in-line” mixers and extruders. Extruders may be single screw ortwin-screw. Twin-screw extruders may turn in the same or oppositedirection.

[1296] Milling may also be employed to prepare the compositions of thepresent invention. Milling is the mechanical process of reducing theparticle size of solids (comminution). Because in some cases milling mayalter crystalline structure and cause chemical changes for somematerials, milling conditions are generally chosen which do not alterthe physical form of the drug/matrix dispersion in the sense that thedrug/matrix dispersion and concentration-enhancing polymer are not, to alarge extent, mixed at the molecular level to form another dispersion ofconcentration-enhancing polymer, and drug and matrix. Thus, thecomposition after milling continues to contain regions rich in thedrug/matrix dispersion and regions rich in concentration-enhancingpolymer. The most common types of milling equipment are the rotarycutter, the hammer, the roller and fluid energy mills. Equipment choicedepends on the characteristics of the ingredients in the drug form(e.g., soft, abrasive, or friable). Wet- or dry-milling techniques canbe chosen for several of these processes, also depending on thecharacteristics of the ingredients (e.g. drug stability in solvent). Themilling process may serve simultaneously as a mixing process if the feedmaterials are heterogeneous. Conventional mixing and milling processessuitable for use in the present invention are discussed more fully inLachman, et al., The Theory and Practice of Industrial Pharmacy (3d Ed.1986).

[1297] The components of the compositions of this invention may also becombined by dry- or wet-granulating processes as long as granulatingconditions are chosen that do not transform a substantial portion of thedrug/matrix dispersion and concentration-enhancing polymer into amolecular dispersion of the drug, matrix and concentration-enhancingpolymer.

[1298] Alternatively, the mixture may be formed by first combining thedrug, matrix and concentration-enhancing polymer and then forming thedispersion in the presence of the concentration-enhancing polymer,resulting in a mixture of the drug/matrix dispersion and theconcentration-enhancing polymer. For example, the drug and matrix may bechosen such that the drug is highly soluble in the matrix and is presentin an amount below the solubility limit of the drug in the matrix. Theconcentration-enhancing polymer may be essentially insoluble in thematrix, or may have a high melting point. In either case, the drug,matrix and concentration-enhancing polymer may be blended together,heated and then cooled to form a drug/matrix dispersion using amelt/congeal process. This yields a solid mixture in which theconcentration-enhancing polymer is suspended as a separate phase. As yetanother example, the concentration-enhancing polymer may be insoluble inthe matrix and partition from the drug and matrix during solventprocessing into a separate domain. In that case, the drug, matrix andconcentration-enhancing polymer may be spray-dried together, resultingin a mixture of drug/matrix dispersion and concentration-enhancingpolymer. In another example, the concentration-enhancing polymer may bedissolved in a solvent in which the drug/matrix dispersion issubstantially insoluble. The drug/matrix dispersion may then besuspended in the solution containing the dissolved polymer. The solventmay then be removed from this suspension, for example by spray drying orevaporation, resulting in a mixture of drug/matrix dispersion andconcentration-enhancing polymer. In all of these methods, theconcentration-enhancing polymer in the resulting mixture exists in adomain that is separate from the drug/matrix dispersion as a separatephase and retains its bulk characteristics.

[1299] In addition to the physical mixtures described above, thecompositions of the present invention may constitute any device orcollection of devices that accomplishes the objective of delivering tothe use environment both the drug/matrix dispersion and theconcentration-enhancing polymer. For example, the composition may be inthe form of a single dosage form in which the dispersion andconcentration-enhancing polymer occupy separate regions within thedosage form. Thus, in the case of oral administration to an animal, thedosage form may constitute a layered tablet wherein one or more layerscomprise the drug/matrix dispersion and one or more other layerscomprise the concentration-enhancing polymer. Alternatively, the dosageform may be a coated tablet wherein the tablet core comprises thedrug/matrix dispersion and the coating comprises theconcentration-enhancing polymer. Yet another alternative is for thedosage form to comprise a coated tablet wherein the tablet corecomprises the concentration-enhancing polymer and the coating comprisesthe drug/matrix dispersion. The dosage form may also be a capsule wherethe wall of the capsule comprises the concentration-enhancing polymerand the drug/matrix dispersion is within the capsule. In addition, thedrug/matrix dispersion and the concentration-enhancing polymer may evenbe present in different dosage forms such as tablets or beads and may beadministered simultaneously or separately as long as both thedrug/matrix dispersion and concentration-enhancing polymer areadministered in such a way that the drug and concentration-enhancingpolymer can come into contact in the use environment. When thedrug/matrix dispersion and the concentration-enhancing polymer areadministered separately it is generally preferable to deliver theconcentration-enhancing polymer prior to the drug.

[1300] As described above, in one embodiment the invention finds utilitywhere it is difficult to form a dispersion of the drug andconcentration-enhancing polymer. Thus, at least a portion, if not all,of the concentration-enhancing polymer is present separate from thedispersion of drug and matrix. In general, a molecular dispersion ofdrug and polymer is one in which the physical properties of the mixture,such as melting point or glass-transition temperature, are transformedfrom those characteristic of the bulk (i.e., undispersed) polymer anddrug. In the compositions of the present invention, as disclosed above,the dispersion and at least a portion of the concentration-enhancingpolymer each retain their individual respective physical properties,such as melting point and/or glass-transition temperature.

[1301] The amount of concentration-enhancing polymer relative to theamount of drug present in the mixtures of the present invention dependson the drug and concentration-enhancing polymer and may vary widely froma drug-to-polymer weight ratio of 0.01 to 5. However, in most cases,except when the drug dose is quite low, e.g., 25 mg or less, it ispreferred that the drug-to-polymer ratio is greater than 0.05 and lessthan 2.5 and often the enhancement in drug concentration or relativebioavailability is observed at drug-to-polymer ratios of 1 or less orfor some drugs even 0.2 or less. In cases where the drug dose is about25 mg or less, the drug-to-polymer weight ratio may be significantlyless than 0.05. In general, regardless of the dose, enhancements in drugconcentration or relative bioavailability increase with decreasingdrug-to-polymer weight ratio. However, due to the practical limits ofkeeping the total mass of a tablet, capsule or suspension low, it isoften desirable to use a relatively high drug-to-polymer ratio as longas satisfactory results are obtained. The maximum drug:polymer ratiothat yields satisfactory results varies from drug to drug and is bestdetermined in the in vitro and/or in vivo dissolution tests discussedbelow.

[1302] In general, to maximize the drug concentration or relativebioavailability of the drug, lower drug-to-polymer ratios are preferred.At low drug-to-polymer ratios, there is sufficientconcentration-enhancing polymer available in solution to ensure theinhibition of the precipitation or crystallization of drug from solutionand, thus, the average concentration of drug is much higher. For highdrug/polymer ratios, not enough concentration-enhancing polymer may bepresent in solution and drug precipitation or crystallization may occurmore readily. However, the amount of concentration-enhancing polymerthat can be used in a dosage form is often limited by the maximum totalmass of the dosage form that is acceptable. For example, when oraldosing to a human is desired, at low drug/polymer ratios the total massof drug and polymer may be unacceptably large for delivery of thedesired dose in a single tablet or capsule. Thus, it is often necessaryto use drug/polymer ratios that are less than those which yield maximumdrug concentration relative bioavailability in specific dosage forms toprovide a sufficient drug dose in a dosage from that is small enough tobe easily delivered to a use environment.

Concentration Enhancement

[1303] The concentration-enhancing polymer is present in a sufficientamount so as to improve the concentration of the drug in a useenvironment relative to a control composition. At a minimum, thecompositions of the present invention provide concentration-enhancementrelative to a control comprising crystalline drug alone. Thus, theconcentration-enhancing polymer is present in a sufficient amount sothat when the composition is administered to a use environment, thecomposition provides improved drug concentration (as described morefully below) relative to a control consisting of an equivalent amount ofcrystalline drug but with no concentration-enhancing polymer present.

[1304] Preferably, the compositions of the present invention provideconcentration-enhancement relative to other compositions containing anequivalent amount of amorphous drug. Thus, the compositions of thepresent invention preferably provide concentration enhancement relativeto an equivalent amount of drug but in undispersed amorphous form alone(if the amorphous form is stable). In more preferred embodiments, thecompositions of the present invention provide concentration-enhancementrelative to an equivalent amount of drug/matrix dispersion but withoutany concentration-enhancing polymer present.

[1305] As used herein, a “use environment” can be either the in vivoenvironment of the GI tract, subdermal, intranasal, buccal, intrathecal,ocular, intraaurial, subcutaneous spaces, vaginal tract, arterial andvenous blood vessels, pulmonary tract or intramuscular tissue of ananimal, such as a mammal and particularly a human, or the in vitroenvironment of a test solution, such as phosphate buffered saline (PBS)or a Model Fasted Duodenal (MFD) solution. Concentration enhancement maybe determined through either in vitro dissolution tests or through invivo tests. It has been determined that enhanced drug concentration inin vitro dissolution tests in Model Fasted Duodenal (MFD) solution orPhosphate Buffered Saline (PBS) is a good indicator of in vivoperformance and bioavailability. An appropriate PBS solution is anaqueous solution comprising 20 mM sodium phosphate (Na₂HPO₄), 47 mMpotassium phosphate (KH₂PO₄), 87 mM NaCl, and 0.2 mM KCI, adjusted to pH6.5 with NaOH. An appropriate MFD solution is the same PBS solutionwherein additionally is present 7.3 mM sodium taurocholic acid and 1.4mM of 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine. In particular, acomposition containing a concentration-enhancing polymer may bedissolution-tested by adding it to MFD or PBS solution and agitating topromote dissolution.

[1306] In one aspect, a composition containing a concentration-enhancingpolymer of the present invention provides a Maximum Drug Concentration(MDC) that is at least 1.25-fold the MDC of at least one of the controlcompositions. In other words, if the MDC provided by the controlcomposition is 100 □g/mL, then a composition of the present inventionprovides an MDC of at least 125 □g/mL. More preferably, the MDC of drugachieved with the compositions of the present invention are at least2-fold, and even more preferably at least 3-fold, that of at least oneof the control compositions.

[1307] Alternatively, the compositions containingconcentration-enhancing polymers of the present invention provide in anaqueous use environment a concentration versus time Area Under The Curve(AUC), for any period of at least 90 minutes between the time ofintroduction into the use environment and about 270 minutes followingintroduction to the use environment that is at least 1.25-fold that ofat least one of the control compositions. More preferably, the AUCachieved with the compositions of the present invention are at least2-fold and more preferably at least 3-fold that of at least one of thecontrol compositions.

[1308] Alternatively, the compositions of the present inventioncontaining concentration-enhancing polymers, when dosed orally to ahuman or other animal, provide an AUC in drug concentration in the bloodplasma or serum that is at least 1.25-fold that observed when one of thecontrol compositions is dosed. More preferably, the AUC in the bloodplasma or serum is at least 2-fold and more preferably at least 3-foldthat observed when one of the control compositions is dosed. Thus, thecompositions of the present invention can be evaluated in either an invitro or in vivo test, or both.

[1309] A typical test to evaluate enhanced drug concentration can beconducted by (1) adding a sufficient quantity of test composition (e.g.,the dispersion and concentration-enhancing polymer) to a test medium(such as PBS or MFD solution), such that if all of the drug dissolved,the theoretical concentration of drug would exceed the equilibriumconcentration of the drug in the test medium by a factor of at least 2;(2) adding an appropriate amount of control composition to an equivalentamount of test medium, and (3) determining whether the measured MDCand/or AUC of the test composition in the test medium is at least1.25-fold that of the MDC and/or AUC provided by the controlcomposition. In conducting such a dissolution test, the amount of testcomposition used is an amount such that if all of the drug dissolved,the drug concentration would be at least 2-fold to 100-fold that of theequilibrium concentration of the drug. The concentration of dissolveddrug is typically measured as a function of time by sampling the testmedium and plotting drug concentration in the test medium vs. time sothat the MDC and/or AUC can be ascertained.

[1310] To avoid drug particulates which would give an erroneousdetermination, the test solution is either filtered or centrifuged.“Dissolved drug” is typically taken as that material that either passesa 0.45 □m syringe filter or, alternatively, the material that remains inthe supernatant following centrifugation. Filtration can be conductedusing a 13 mm, 0.45 □m polyvinylidine difluoride syringe filter sold byScientific Resources under the trademark TITAN7. -Centrifugation istypically carried out in a polypropylene microcentrifuge tube bycentrifuging at 13,000 G for 60 seconds. Other similar filtration orcentrifugation methods can be employed and useful results obtained. Forexample, using other types of microfilters may yield values somewhathigher or lower (±10-40%) than that obtained with the filter specifiedabove but will still allow identification of preferred compositions. Itis recognized that this definition of “dissolved drug” encompasses notonly monomeric solvated drug molecules but also a wide range of speciessuch as polymer/drug assemblies that have submicron dimensions such asdrug aggregates, aggregates of mixtures of polymer and drug, micelles,polymeric micelles, colloidal particles or nanocrystals, polymer/drugcomplexes, and other such drug-containing species that are present inthe filtrate or supernatant in the specified dissolution test.

[1311] Alternatively, the compositions of the present invention provideimproved relative bioavailability. Relative bioavailability of the drugin the compositions of the present invention can be tested in vivo inanimals or humans using conventional methods for making such adetermination. An in vivo test, such as a crossover study, may be usedto determine whether a test composition provides an enhanced relativebioavailability compared with a control composition. In an in vivocrossover study a “test composition” of dispersion andconcentration-enhancing polymer is dosed to half a group of testsubjects and, after an appropriate washout period (e.g., one week) thesame subjects are dosed with a “control composition.” The “controlcomposition” may be any of the control compositions described earlier.The other half of the group is dosed with the control composition first,followed by the test composition. The relative bioavailability ismeasured as the concentration in the blood (serum or plasma) versus timearea under the curve (AUC) determined for the test group divided by theAUC in the blood provided by the control composition. Preferably, thistest/control ratio is determined for each subject, and then the ratiosare averaged over all subjects in the study. In vivo determinations ofAUC can be made by plotting the serum or plasma concentration of drugalong the ordinate (y-axis) against time along the abscissa (x-axis).Generally, the values for AUC represent a number of values taken fromall of the subjects in a patient test population averaged over theentire test population.

[1312] A preferred embodiment of the invention is one in which therelative bioavailability of the test composition is at least 1.25relative to at least one of the control compositions. (That is, the AUCin the blood provided by the test composition is at least 1.25-fold theAUC provided by the control composition.) An even more preferredembodiment of the invention is one in which the relative bioavailabilityof the test composition is at least 2.0 relative to at least one of thecontrol compositions. The determination of AUCs is a well-knownprocedure and is described, for example, in Welling, “PharmacokineticsProcesses and Mathematics,” ACS Monograph 185 (1986).

[1313] Often the enhancement in drug concentration or relativebioavailability that is observed increases as the drug:concentration-enhancing polymer ratio decreases from a value of about 1to a value of about 0.1. The drug:polymer ratio that yields optimumresults varies from drug to drug and is best determined in in vitrodissolution tests and/or in vivo-bioavailability tests. However, theamount of concentration-enhancing polymer that can be used in a dosageform is often limited by the total mass requirements of the dosage formas described above.

[1314] While not wishing to be bound by a particular theory, it isbelieved that while the concentration-enhancing polymer(s) of thepresent invention may to some extent solubilize insoluble drugs (thatis, to increase the equilibrium concentration of free drug), theconcentration-enhancing polymers also act to slow the rate ofprecipitation or crystallization of the drug after the drug is initiallydissolved. The presence of the concentration-enhancing polymer(s) thusallows the initially increased or enhanced concentration provided by thedrug/matrix dispersion to be at least partially maintained for at leasta few minutes and, in some cases, for many hours. In addition, in caseswhere dissolution of the drug is slow and precipitation of thecrystalline drug, in the absence of the concentration-enhancing polymer,is fast, the presence of the concentration-enhancing polymer may resultin the maximum concentration of drug observed being substantially higherthan that observed in the absence of the concentration-enhancingpolymer.

[1315] One possible mechanism for improving the drug concentrationinvolves the association of the concentration-enhancing polymer anddissolved drug to form “polymer/drug assemblies.” Such assemblies mayconstitute various forms, including polymeric micelles, high-energypolymer-drug aggregates ranging in size from a few nanometers to 1000nanometers, polymer-stabilized drug colloids or polymer/drug complexes.An alternative view is that as dissolved drug begins to precipitate orcrystallize from solution (e.g., as nucleation begins) the polymeradsorbs to these drug aggregates or nuclei, preventing, or at leastretarding, the nucleation or crystal-growth process. In any case, thepresence of the polymer serves to enhance the amount of drug that isdissolved or at least available for absorption. Drug present in thevarious drug/polymer assemblies listed above is apparently quite labileand may contribute to the drug absorption process.

Excipients and Dosage Forms

[1316] Although the key ingredients present in the compositions of thepresent invention are simply the drug/matrix dispersion combined withthe concentration-enhancing polymer(s), the inclusion of otherexcipients in the composition may be useful. These excipients may beutilized with the dispersion/polymer mixture in order to formulate themixture into tablets, capsules, suspensions, powders for suspension,creams, transdermal patches, depots, and the like. In addition, asdescribed above, the drug/matrix dispersion and theconcentration-enhancing polymer may be mixed with excipients separatelyto form different beads, or layers, or coatings, or cores or evenseparate dosage forms.

[1317] One very useful class of excipients is surfactants. Suitablesurfactants include fatty acid and alkyl sulfonates; commercialsurfactants such as benzethanium chloride (HYAMINE7 1622, available fromLonza, Inc., Fairlawn, N.J.); DOCUSATE SODIUM (available fromMallinckrodt Spec. Chem., St. Louis, Mo.); polyoxyethylene sorbitanfatty acid esters (TWEEN7, available from ICI Americas Inc., Wilmington,Del.); LIPOSORB7 P-20 (available from Lipochem Inc., Patterson N.J.);CAPMUL7 POE-0 (available from Abitec Corp., Janesville, Wis.), andnatural surfactants such as sodium taurocholic acid,1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, lecithin, and otherphospholipids and mono- and diglycerides. Such materials canadvantageously be employed to increase the rate of dissolution byfacilitating wetting, thereby increasing the maximum dissolvedconcentration, and also to inhibit crystallization or precipitation ofdrug by interacting with the dissolved drug by mechanisms such ascomplexation, formation of inclusion complexes, formation of micelles oradsorbing to the surface of solid drug. These surfactants may compriseup to 5 wt % of the composition.

[1318] The addition of pH modifiers such as acids, bases, or buffers mayalso be beneficial, retarding the dissolution of the composition (e.g.,acids such as citric acid or succinic acid when the polymer is anionic)or, alternatively, enhancing the rate of dissolution of the composition(e.g., bases such as sodium acetate or amines when the polymer isanionic).

[1319] Other conventional formulation excipients may be employed in thecompositions of this invention, including those excipients well-known inthe art (e.g., as described in Remington's Pharmaceutical Sciences(16^(th) ed. 1980). Generally, excipients such as fillers,disintegrating agents, pigments, binders, lubricants, glidants,flavorants, and so forth may be used for customary purposes and intypical amounts without adversely affecting the properties of thecompositions. These excipients may be utilized after the drug/polymercomposition has been formed, in order to formulate the composition intotablets, capsules, suspensions, powders for suspension, creams,transdermal patches, and the like.

[1320] Examples of other matrix materials, fillers, or diluents includelactose, mannitol, xylitol, dextrose, sucrose, sorbitol, compressiblesugar, microcrystalline cellulose, powdered cellulose, starch,pregelatinized starch, dextrates, dextran, dextrin, dextrose,maltodextrin, calcium carbonate, dibasic calcium phosphate, tribasiccalcium phosphate, calcium sulfate, magnesium carbonate, magnesiumoxide, poloxamers such as polyethylene oxide, and hydroxypropyl methylcellulose.

[1321] Examples of surface active agents include sodium lauryl sulfateand polysorbate 80.

[1322] Examples of drug complexing agents or solubilizers include thepolyethylene glycols, caffeine, xanthene, gentisic acid andcylodextrins.

[1323] Examples of disintegrants include sodium starch glycolate, sodiumcarboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellosesodium, crospovidone (crosslinked polyvinyl pyrrolidone), methylcellulose, microcrystalline cellulose, powdered cellulose, starch,pregelatinized starch, and sodium alginate.

[1324] Examples of tablet binders include acacia, alginic acid,carbomer, carboxymethyl cellulose sodium, dextrin, ethylcellulose,gelatin, guar gum, hydrogenatetd vegetable oil, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methylcellulose, liquid glucose, maltodextrin, polymethacrylates, povidone,pregelatinized starch, sodium alginate, starch, sucrose, tragacanth, andzein.

[1325] Examples of lubricants include calcium stearate, glycerylmonostearate, glyceryl palmitostearate, hydrogenated vegetable oil,light mineral oil, magnesium stearate, mineral oil, polyethylene glycol,sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearicacid, talc, and zinc stearate.

[1326] Examples of glidants include silicon dioxide, talc andcornstarch.

[1327] Compositions of this invention may be used in a wide variety ofdosage forms for administration of drugs. Exemplary dosage forms arepowders or granules that may be taken orally either dry or reconstitutedby addition of water to form a paste, slurry, suspension or solution;tablets; capsules; multiparticulates; and pills. Various additives maybe mixed, ground, or granulated with the compositions of this inventionto form a material suitable for the above dosage forms.

[1328] In some cases, the overall dosage form or particles, granules orbeads that make up the dosage form may have superior performance ifcoated with an enteric polymer to prevent or retard dissolution untilthe dosage form leaves the stomach. Exemplary enteric coating materialsinclude HPMCAS, HPMCP, CAP, CAT, carboxymethylethyl cellulose,carboxylic acid-functionalized polymethacrylates, and carboxylicacid-functionalized polyacrylates.

[1329] Compositions of this invention may be administered in acontrolled release dosage form. In one such dosage form, the compositionof the drug/matrix dispersion and concentration-enhancing polymer isincorporated into an erodible polymeric controlled-release matrixdevice. By an erodible controlled-release matrix is meantaqueous-erodible or water-swellable or aqueous-soluble in the sense ofbeing either erodible or swellable or dissolvable in pure water orrequiring the presence of an acid or base to ionize the polymericcontrolled-release matrix sufficiently to cause erosion or dissolution.When contacted with the aqueous environment of use, the erodiblepolymeric controlled-release matrix imbibes water and forms anaqueous-swollen gel or “matrix” that entraps the mixture of drug/matrixdispersion and concentration-enhancing polymer. The aqueous-swollencontrolled-release matrix gradually erodes, swells, disintegrates ordissolves in the environment of use, thereby controlling the release ofthe drug mixture to the environment of use.

[1330] Alternatively, the compositions of the present invention may beadministered by or incorporated into a non-erodible controlled-releasematrix device.

[1331] Alternatively, the drug mixture of the invention may be deliveredusing a coated osmotic controlled release dosage form. This dosage formhas two components: (a) the core which contains an osmotic agent and thedrug/matrix dispersion; and (b) a coating surrounding the core, thecoating controlling the influx of water to the core from an aqueousenvironment of use so as to cause drug release by extrusion of some orall of the core to the environment of use. The osmotic agent containedin the core of this device may be an aqueous-swellable hydrophilicpolymer, hydrogel, osmogen, or osmagent. The coating is preferablypolymeric, aqueous-permeable, and has at least one delivery port. Theconcentration-enhancing polymer may be either mixed with the drug/matrixdispersion or be in a separate region of the core or it may be appliedas a second coating over the coating that controls the influx of water.

[1332] Alternatively, the drug mixture of the invention may be deliveredvia a coated hydrogel controlled release dosage form having threecomponents: (a) a drug-containing composition containing the drug/matrixdispersion, (b) a water-swellable composition wherein thewater-swellable composition is in a separate region within a core formedby the drug-containing composition and the water-swellable composition,and (c) a coating around the core that is water-permeable, and has atleast one delivery port therethrough. In use, the core imbibes waterthrough the coating, swelling the water-swellable composition andincreasing the pressure within the core, and fluidizing thedrug-containing composition. Because the coating remains intact, thedrug-containing composition is extruded out of the delivery port into anenvironment of use. The concentration-enhancing polymer may be deliveredin a separate dosage form, may be included in the drug-containingcomposition, may be included in the water-swellable composition, may beincluded in a separate layer within the core, or may constitute all orpart of a coating applied to the dosage form.

[1333] Alternatively, the compositions of the present invention may beco-administered, meaning that the dispersion can be administeredseparately from, but within the same general time frame as, theconcentration-enhancing polymer. Thus, a dispersion can, for example, beadministered in its own dosage form which is taken at approximately thesame time as the concentration-enhancing polymer which is in a separatedosage form. If administered separately, it is generally preferred toadminister both the dispersion and the concentration-enhancing polymerwithin 60 minutes of each other, so that the two are present together inthe environment of use. When hot administered simultaneously, theconcentration-enhancing polymer is preferably administered prior to thedispersion.

[1334] In addition to the above additives or excipients, use of anyconventional materials and procedures for preparation of suitable dosageforms using the compositions of this invention known by those skilled inthe art are potentially useful.

[1335] Other features and embodiments of the invention will becomeapparent from the following examples which are given for illustration ofthe invention rather than for limiting its intended scope.

EXAMPLES

[1336] Example 1

[1337] A solid drug/matrix dispersion was prepared by forming anamorphous solid dispersion of 25 wt % of the low-solubility,acid-sensitive drug quinoxaline-2-carboxylic acid[4(R)-carbamoyl-I(S)-3-fluorobenzyl)-2(S),7-dihydroxy-7-methyl-octyl]amide(“Drug 1”) and 75 wt % polydextrose. The dispersion was made by firstmixing Drug 1 in a 3/1 methanol/water solvent together with polydextrose(Litesse Ultra7, manufactured by Cultor Food Science, Inc., Ardsley,N.Y.) to form a solution. The solution comprised 1.3 wt % Drug 1, 3.8 wt% polydextrose, and 94.9 wt % 3/1 (wt/wt) methanol/water. This solutionwas pumped into a “mini” spray-dryer apparatus via a syringe pump at arate of 30 mL/hr. The spray solution was metered using a Cole Parmer74900 series rate-controlling syringe pump. The solution was atomizedthrough a Spraying Systems Company two-fluid nozzle, model number SU1A,with nitrogen as the atomizing gas. The nitrogen was pressurized andheated to a temperature of 115° C. The solution was sprayed from the topof an 11-cm diameter stainless steel chamber. The resulting solidamorphous dispersion was collected on a Whatman7 1 filter paper at ayield of about 54%, dried under vacuum, and stored in a dessicator.

[1338] Example 1 was prepared by combining the solid dispersion with theconcentration-enhancing polymer HPMCAS. 14.4 mg of the dispersion wasadded to two respective microcentrifuge tubes. The tubes were eachplaced in a 37° C. sonicating bath, and 1.8 mL phosphate buffered saline(PBS) with 14.4 mg HPMCAS-HF at pH 6.5 and 290 mOsm/kg was added to eachtube. The samples were quickly mixed using a vortex mixer for about 60seconds. The samples were centrifuged at 12,000 G at 37° C. for 1minute. The resulting supernatant solution was then sampled and diluted1:6 (by volume) with methanol and then analyzed by high-performanceliquid chromatography (HPLC). The contents of the tubes were mixed onthe vortex mixer and allowed to stand undisturbed at 37° C. until thenext sample was taken. Samples were collected at 4, 10, 20, 40, 90, 180and 1200 minutes. The average concentrations of drug obtained in thesesamples are shown in Table 1 below.

[1339] Similarly, a control composition C1 was prepared comprising thesame dispersion as Example 1 but without the concentration-enhancingpolymer HPMCAS. An in vitro dissolution test was performed using theprocedures described for Example 1 except that 14.4 mg of the dispersionwas tested without the concentration-enhancing polymer (HPMCAS) in thetest solution.

[1340] A control composition C2 comprising amorphous Drug 1 alone (thatis, undispersed amorphous Drug 1) was also prepared. A dissolution testwas performed using the procedures described for Example 1 except that3.6 mg of the amorphous drug was tested without theconcentration-enhancing polymer in the test solution. The concentrationsof drug obtained in in vitro dissolution tests are shown below inTable 1. TABLE 1 Drug 1 Time Conc. AUC Example (min) (μg/mL) (min*μg/mL)1 0 0 0 4 903 1,800 10 1299 8,400 20 1436 22,100 40 1542 51,900 90 1548129,100 180 1591 270,400 1200 1646 1,921,200 C1  0 0 0 4 723 1,400 10947 6,500 20 1097 16,700 40 1249 40,100 90 1114 99,200 180 750 183,1001200 426 782,900 C2 0 0 0 4 619 1,200 10 841 5,600 20 947 14,600 40 102834,300 90 1104 87,600 1200 706 1,092,200

[1341] The results of this test are summarized in Table 2, which showsthe maximum concentration of Drug 1 in solution in Example 1 during thefirst 90 minutes of the test (C_(max,90)), the area under the aqueousconcentration versus time curve after 90 minutes (AUC₉₀), and theconcentration at 1200 minutes (C₁₂₀₀). TABLE 2 Drug 1 Conc. in theConc.- C_(max,90) AUC₉₀ Matrix Dispersion Enhancing (μg/ (min*μg/ C₁₂₀₀Ex. Material (wt %) Polymer mL) mL) (μg/mL) 1 Polydex- 25 HPMCAS 1548129,100 1646 trose C1 Polydex- 25 none 1249 99,200 426 trose C2 none Cnone 1104 87,600 706

[1342] The results, summarized in Table 2, show that the performance ofthe composition of Example 1 containing concentration-enhancing polymerwas much better than that of the dispersion alone. The C_(max90) ofExample 1 was 1.24-fold that of control C1, and AUC₉₀ was 1.30-fold thatof C1. In addition, the dissolved drug concentration at 1200 minutes (20hours) for the test composition was 3.9-fold that of the Control C1,showing that the composition sustained higher concentration of drug fora longer period of time. The C_(max90) of Example 1 was 1.40-fold thatof control C2, and AUC₉₀ was 1.47-fold that of C2. In addition, thedissolved drug concentration at 1200 minutes (20 hours) for the testcomposition was 2.33-fold that of the Control C2.

[1343] Example 2

[1344] This example discloses a composition comprising a drug/matrixdispersion of an acid-sensitive drug, Drug 1, and an acidicconcentration-enhancing polymer which has improved chemical stability.Example 2 was prepared by mixing 25 wt % of the drug/matrix dispersioncontaining Drug 1 (an acid-sensitive drug) formed in Example 1 with 75wt % of the acidic concentration-enhancing polymer HPMCAS. Thecomposition of Example 2 was then placed in a controlled-atmospherechamber maintained at 40° C. and 75% RH for 10 days. Drug 1 potencies ofthe composition before and after storage were determined using HPLC.Drug 1 potency was the percent of the total HPLC peak area correspondingto the amount of drug originally present in the dispersion prior tostorage. The results are shown in Table 3 below.

[1345] A control composition, C3, comprising a dispersion of Drug 1 withHPMCAS-LF was made by preparing a solution containing 0.33 wt % Drug 1and 1.0 wt % HPMCAS-LF in acetone, and spray-drying the solution usingthe “mini” spray-dryer apparatus described in Example 1, except that thenitrogen was heated to 100° C. Control C3 was placed in acontrolled-atmosphere chamber maintained at 40° C. and 75% RH for 14days and Drug 1 potencies of the composition before and after storagewere determined using HPLC as described above. The results are shown inTable 3. TABLE 3 Potency Degree of Potency Day 10 Degradation Ex- Conc.-Before at 40° C./ Day 10 ample Matrix Enhancing Storage 75% RH 40°C./75% No. Material Polymer (wt %) (wt %) RH (wt %) 2 Polydex- HPMCAS-100 88 12  trose LG C3 HPMCAS- None 94  <1* >93* LF

[1346] As can be seen from the data in Table 3, the composition ofExample 2 provided improved chemical stability for Drug 1 compared withthe Control C3, which was a dispersion of Drug 1 in the acidicconcentration-enhancing polymer.

[1347] Examples 3 and 4

[1348] These examples demonstate drug/matrix dispersions formed usingDrug 1 but with different matrix materials. Solid drug/matrixdispersions were prepared using the procedure described in Example 1with the following exceptions. The matrix for Example 3 waspolyvinylalcohol (PVA) and for Example 4 used to form the spray solutionfor Drug 1 and PVA and 4/1 methanol/water, and the solvent used to formthe spray soltion of Drug 1 and dextran was 3/2 water/methanol. Thenitrogen was heated to 100° C. for Example 3 and 130° C. for Example 4.The yields were 61% for the PVA dispersion and 52% for the dextrandispersion.

[1349] Example 3 was prepared by mixing 14.4 mg of the PVA dispersionwith 14.4 mg HPMCAS-HF, while Example 4 was prepared by mixing 14.4 mgof the dextran dispersion with 14.4 mg of of HPMCAS-HF. In vitrodissolution tests of Examples 3 and 4 were performed using the proceduredescribed in Example 1.

[1350] Control C2 was simple amorphous drug alone used in thedissolution test described in Example 1. Controls C4 and C5 wereprepared using 14.4 mg of the same dispersions as Examples 3 and 4,respectfully, but without the concentration-enhancing polymer. In vitrodissolution tests were performed using the procedures described inExample 1. The concentrations of drug obtained in in vitro dissoutiontests are shown below.

[1351] The results are presented in Table 4 and summarized in Table 5.TABLE 4 Drug 1 Time Concentration AUC Example (min) (μg/mL) (min*μg/mL)3 0 0 0 4 1365 2,700 10 1441 11,100 20 1399 25,400 40 1577 55,100 901541 133,000 180 1648 276,500 1200 1863 2,067,200 4 0 0 0 4 1179 2,40010 1093 9,200 20 1164 20,500 40 1161 43,700 90 1441 108,800 180 1619246,500 1200 2196 2,192,100 C4  0 0 0 4 1554 3,100 10 1860 13,300 201474 30,000 40 744 52,200 90 685 87,900 180 632 147,200 1200 580 765,300C5  0 0 0 4 949 1,900 10 1021 7,800 20 1169 18,800 40 1237 42,800 90 96497,800 180 511 164,200 1200 454 656,400

[1352] The results of this test are summarized in Table 5, which showsthe maximum concentration of Drug 1 in solution during the first 90minutes of the test (C_(max90)), the area under the aqueousconcentration versus time curve after 90 minutes (AUC₉₀), and theconcentration at 1200 minutes (C₁₂₀₀). Dissolution test results for Drug1 dispersions described in Examples 3 and 4 and Controls C2, C3 and C4,are all shown in Table 5 for comparison. TABLE 5 Drug 1 Conc. in theConc.- C_(max,90) AUC₉₀ Matrix Dispersion Enhanc. (μg/ (min*μg/ C₁₂₀₀Ex. Material (wt %) Polymer mL) mL) (μg/mL) 3 PVA 25 HPMCAS 1541 133,0001863 4 Dextran 25 HPMCAS 1441 108,800 2196 C2 none C none 1104 87,600706 C4 PVA 25 none 1860 87,900 580 C5 Dextran 25 none 1237 97,800 454

[1353] The results, summarized in Table 5, show that the performance ofthe compositions of Examples 3 and 4 containing concentration-enhancingpolymer were better than that of the controls. For Example 3, theC_(max90) was 1.4-fold that of Control C2 (undispersed amorphous drug),and the AUC₉₀ was 1.5-fold that of Control C2. In addition, Example 3provided an AUC₉₀ that was 1 .5-fold that of Control C4, the drug/matrixdispersion without concentration-enhancing polymer. For Example 4, theC_(max90) was 1.3-fold that of Control C2, and the AUC₉₀ was 1.24-foldthat of Control C2. In addition, Example 4 provided a C_(max90) that was1.16-fold that of Control C5 (the drug/matrix dispersion withoutconcentration-enhancing polymer), and an AUC₉₀ that was 1.11-fold thatof Control C5.

[1354] Example 5

[1355] This example demonstrates a drug/matrix dispersion with anotherdrug. A solid drug/matrix dispersion comprised of 10 wt %3,5-dimethyl-4-(3′-pentoxy)-2-(2′, 4′, 6′-trimethylphenoxy) pyridine(“Drug 2”) and 90 wt % polyethylene glycol was prepared by amelt-congeal process. 4.5 gm polyethylene glycol 3350 (PEG 3350 UnionCarbide Corp.) was heated in a 70° C. oven to obtain a clear liquid, and0.5 g of Drug 2 was added. Following addition of Drug 2, the melt wasstirred and returned to the 70° C. oven for 2.5 hours. Next, the meltwas cooled to room termperature and ground in a mortar and pestle usingliquid nitrogen. The resulting solid amorphous dispersion contained 10wt % Drug 2.

[1356] Example 5 was prepared by combining the drug/matrix dispersion ofDrug 2 and polyethylene glycol with the concentration-enhancing polymerHPMCAS. Example 5 was evaluated in an in vitro dissolution test using amicrocentrifuge method. In this test, 18 mg of the dispersion was addedto each of two microcentrifuge tubes. The tubes were placed in a 37° C.temperature-controlled chamber, and 1.8 mL PBS containing 7.3 mM sodiumtaurocholic acid and 1.4 mM1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine, with 7.2 mg HPMCAS-MF,was added. The tests were sampled as described in Example 1, andanalyzed using HPLC. Samples were collected at 4, 10, 20, 40, 90, and1200 minutes. The results are presented in Table 6 and 7.

[1357] For control C6, in vitro tests were performed using theprocedures described in Example 1 except that 18 mg of the dispersion ofExample 5 was tested without concentration-enhancing polymer (HPMCAS) inthe test solution. The concentrations of drug obtained in the in vitrodissolution test are shown in Table 6. For Control C7, the amorphousform of Drug 2 could not be isolated beause it rapidly converted to thecrystalline form. Thus, for Control C7, 1.8 mg of crystalline Drug 2 wastested (without concentration-enhancing polymer in the test solution).TABLE 6 Drug 2 Time Concentration AUC Example (min) (μg/mL) (min*μg/mL)5 0 0 0 4 74 100 10 93 600 20 90 1,600 40 68 3,100 90 59 6,300 1200 5871,300 C6  0 0 0 4 83 200 10 80 700 20 72 1400 40 56 2,700 90 50 5,3001200 51 61,400 C7  0 0 0 4 16 0 10 33 200 20 32 500 40 30 1,100 90 392,800 1200 37 45,000

[1358] The results of this test are summarized in Table 7, which showsthe maximum concentration of Drug 2 in solution during the first 90minutes of the test (C_(max90)), the area under the aqueousconcentration versus time curve after 90 minutes (AUC₉₀), and theconcentration at 1200 minutes (C₁₂₀₀). Dissolution test results for Drug2 dispersions described in Example 5 and Controls C6 and C7, are allshown in Table 7 for comparison. TABLE 7 Drug 2 Conc. Concen- in thetration C_(max,90) AUC₉₀ Ex- Matrix Dispersion Enhanc. (μg/ (min* C₁₂₀₀ample Material* (wt %) Polymer* mL) μg/mL) (μg/mL) 5 PEG 3350 10 HPMCAS93 6300 58 C6 PEG 3350 10 None 83 5300 51 C7 none C None 39 2800 37

[1359] These results show that the addition of concentration-enhancingpolymer increased the C_(max90), AUC₉₀, and C₁₂₀₀ for Drug 2 over thatof the dispersion and crystalline drug alone. Example 5 provided aC_(max,90) that was 1.12-fold, and an AUC₉₀ that was 1.19-fold thatprovided by Control C6, and a C_(max90) that was 2.38-fold, and an AUC₉₀that was 2.25-fold that provided by Control C7.

[1360] Example 6

[1361] This example discloses yet another low-solubility drug. Adrug/matrix dispersion of amorphous drug and matrix was prepared byforming an amorphous dispersion of 25 wt % [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester (“Drug 3”) and 75 wt % PVP. The dispersion was formedby spray-drying a solution containing 0.96 wt % Drug 3 and 2.89 wt % PVPin acetone, using a “mini” spray-drier as described in Example 1, exceptthat the nitrogen was heated to 100° C. The resulting dispersioncontained 25 wt % Drug 3.

[1362] Example 6 was prepared by combining the dispersion with theconcentration-enhancing polymer HPMCAS. 7.2 mg of the dispersion ofExample 6 was added to microcentrifuge tubes. Tests were performed induplicate. The tubes were placed in a 37° C. temperature-controlledchamber, and 1.8 mL PBS with 5.4 mg HPMCAS-MF was added. The tests weresampled as described in Example 1, and analyzed using HPLC.

[1363] For Control C8, in vitro dissolution tests were performed usingthe procedures described above except that 7.2 mg of the amorphousdispersion of Example 6 was tested without concentration-enhancingpolymer (HPMCAS) in the test solution. The concentrations of drugobtained in the in vitro dissolution test are shown in Table 7.

[1364] For Control C9, 1.8 mg of undispersed amorphous Drug 3 was tested(without concentration-enhancing polymer in the test solution) using theprocedures described above. TABLE 8 Drug 3 Time Concentration AUCExample (min) (μg/mL) (min*μg/mL) 6 0 0 0 4 51 100 10 40 400 20 37 80040 39 1,500 90 31 3,300 1200 13 27,700 C8  0 0 0 4 29 100 10 16 200 2011 300 40 7 500 90 0 700 1200 0 700 C9  0 <1 <1 4 <1 <1 10 <1 <1 20 <1<1 40 <1 <1 90 <1 <1 1200 <1 <1

[1365] The concentrations of drug obtained in in vitro dissolution testsare shown in Table 8. Results from dissolution tests of Example 6, andControls C8 and C9, are summarized in Table 9. TABLE 9 Drug 3 Conc.Concen- in the tration C_(max,90) AUC₉₀ Ex- Matrix Dispersion Enhanc.(μg/ (min* C₁₂₀₀ ample Material* (wt %) Polymer* mL) μg/mL) (μg/mL) 6PVP 25 HPMCAS 51 3300 13 C8 PVP 25 None 29 700 <1 C9 none C None <1 <1<1

[1366] These results show that the performance of Example 6 containing adrug/matrix dispersion and concentration-enhancing polymer was muchbetter than that of the dispersion alone (Control C8) and undispersedamorphous drug (Control C9). The C_(max90) of Example 6 was 1.8-foldthat of Control C8, and the AUC₉₀ was 4.7-fold that of C8, and theC_(max90) of Example 6 was at least 51-fold that of Control C9, and theAUC₉₀ was at least 3300-fold that of C9.

[1367] Examples 7 and 8

[1368] This example discloses the use of other concentration-enhancingpolymers to obtain improved performance. The Drug 3/PVP drug/matrixdispersion of Example 6 is mixed with concentration-enhancing polymersto form a composition of the present invention. For the composition ofExample 7, about 30 wt % to 80 wt % of the Drug 3/PVP dispersion ismixed with 70 wt % to 20 wt % cellulose acetate phthalate (CAP) to forma solid physical mixture. For the composition of Example 8, about 30 wt% to 80 wt % of the Drug 3/PVP dispersion is mixed with about 70 wt % to20 wt % hydroxypropyl methyl cellulose (HPMC) to form a solid physicalmixture.

[1369] In vitro dissolution tests are performed using the compositionsof Examples 7 and 8 as follows. A sample of each of the compositionscontaining 1.8 mg of Drug 3 is added to microcentrifuge tubes. The tubesare placed in a 37° C. temperature-controlled chamber, and 1.8 mL PBS isadded. The solutions are then sampled as described in Example 1 andanalyzed using HPLC.

[1370] Example 9

[1371] A drug/matrix dispersion was prepared by forming an amorphousdispersion of 25 wt % 5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-3-((3R,4S)-dihydroxypyrrolidin-1-yl-)-(2R)-hydroxy-3-oxypropyl] amide (“Drug4”) and 75 wt % PVP. The dispersion was formed by spray-drying asolution containing 0.33 wt % Drug 4 and 0.99 wt % PVP in acetone, usinga “mini” spray-drier as described in Example 1, except that the nitrogenwas heated to 100° C. The resulting dispersion contained 25 wt % Drug 4.

[1372] Example 9 was prepared by combining the above amorphousdispersion with the concentration-enhancing polymer PVA (polyvinylacetate/polyvinyl alcohol, 88% hydrolyzed, average molecular weight85,000-146,000; Aldrich Chemical Co.). 14.4 mg of the dispersion ofExample 9 was added to microcentrifuge tubes. Tests were performed induplicate. The tubes were placed in a 37° C. temperature-controlledchamber, and 1.8 mL PBS with 7.2 mg PVA was added. The tests weresampled as described in Example 1, and analyzed using HPLC. HPLCanalysis was performed using a Zorbax SB C₁₈ column, with a mobile phaseof 35 vol. % water and 65 vol. % methanol. UV absorbance of Drug 4 wasmeasured at 297 nm.

[1373] For Control C10, in vitro dissolution tests were performed usingthe procedures described above except that 14.4 mg of the amorphousdispersion of Example 9 was tested without concentration-enhancingpolymer (PVA) in the test solution.

[1374] For Control C11, 3.6 mg of undispersed amorphous Drug 4 wastested (without concentration-enhancing polymer in the test solution)using the procedures described above. The concentrations of drugobtained in in vitro dissolutions tests are shown in Table 10. TABLE 10Drug 4 Time Concentration AUC Example (mins) (μg/mL) (min*μg/mL)  9 0 00 4 907 1,800 10 939 7,400 20 983 17,000 40 980 36,600 90 980 85,6001200 1028 1,200,000 C10 0 0 0 4 739 1,500 10 731 5,900 20 726 13,200 40715 27,600 90 697 62,900 1200 674 823,800 C11 0 0 0 4 360 700 10 3822,900 20 372 6,700 40 345 13,900 90 262 29,100 1200 154 259,800

[1375] Results from dissolution tests of Example 9, and Controls C10 andC11, are summarized in Table 11. TABLE 11 Drug 4 Conc. in the Conc.C_(max,90) AUC₉₀ Ex- Matrix Dispersion Enhancing (μg/ (min* C₁₂₀₀ ampleMaterial* (wt %) Polymer* mL) μg/mL) (μg/mL) 9 PVP 25 PVA 983 85,6001028 C10 PVP 25 none 739 62,900 674 C11 None — none 382 29,100 154

[1376] These results show that Example 9 consisting of a drug/matrixdispersion and concentration-enhancing polymer providedconcentration-enhancement relative to the dispersion alone (Control C10)and undispersed amorphous drug (Control C11). The C_(max90) of Example 9was 1.33-fold that of control C10, and the AUC₉₀ was 1.36-fold that ofC10. The C_(max90) of Example 9 was 2.57-fold that of control C11, andthe AUC₉₀ was 2.94-fold that of C11.

[1377] Example 10

[1378] This example discloses another low-solubility drug. A drug/matrixdispersion of amorphous drug and matrix was prepared by forming anamorphous dispersion of 25 wt %5-(2-(4-(3-benzisothiazolyl)-piperazinyl)ethyl-6-chlorooxindole mesylate(“Drug 5”) and 75 wt % PVP. The dispersion was formed by spray-drying asolution containing 0.5 wt % Drug 5 and 0.5 wt % PVP in methanol, usinga “mini” spray-drier as described in Example 1, except that the nitrogenwas heated to 120° C. The resulting amorphous dispersion contained 50 wt% Drug 5.

[1379] Example 10 was prepared by combining the above amorphousdispersion with the concentration-enhancing polymer hydroxypropylmethylcellulose (HPMC E3 Prem LV, Dow Chemical Co.). 1.4 mg of theamorphous dispersion was added to microcentrifuge tubes. The tubes wereplaced in a 37° C. temperature-controlled chamber, and 1.8 mL PBScontaining 0.5 wt % sodium taurocholicacid/1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine (MFDS, pH 6.5) and0.4 mg HPMC was added. The tests were sampled as described in Example 1,and analyzed using HPLC.

[1380] For Control C12, in vitro dissolution tests were performed usingthe precedures described above except that 1.4 mg of the amorphousdispersion was tested without concentration-enhancing polymer (HPMC) inthe test solution.

[1381] For Control C13, 0.44 mg of undispersed amorphous Drug 5 wastested (without concentration-enhancing polymer in the test solution)using the procedures described above. The concentrations of drugobtained in in vitro dissolution tests are shown in Table 12. TABLE 12Drug 5 Time Concentration AUC Example (mins) (μg/mL) (min*μg/mL) 10 0 00 4 162 300 10 35 900 20 33 1,300 40 13 1,700 90 10 2,300 1200 10 13,400C12  0 0 0 4 10 0 10 13 100 20 16 200 40 15 500 90 7 1,100 1200 3021,600 C13  0 0 0 4 16 0 10 8 100 20 5 200 40 4 300 90 4 500 1200 44,900

[1382] Results from dissolution tests of Example 10, and Controls C12and C13, are summarized in Table 13. TABLE 13 Drug 5 Conc. in the Conc.C_(max,90) AUC₉₀ Ex- Matrix Dispersion Enhanc. (μg/ (min* C₁₂₀₀ ampleMaterial* (wt %) Polymer* mL) μg/mL) (μg/mL) 10 PVP 50 HPMC 162 2300 10C12 PVP 50 none 16 1100 30 C13 None — none 16 500 4

[1383] These results show that the composition of Example 10, consistingof a drug/matrix dispersion and concentration-enhancing polymer providedconcentration-enhancement relative to the dispersion alone (Control C12)and undispersed amorphous drug (Control C13). The C_(max90) Example 10was 10-fold that of Control C12, and the AUC₉₀ was 2.1-fold that ofControl C12. The C_(max90) of Example 10 was 10-fold that of ControlC13, and the AUC₉₀ was 4.6-fold that of Control C13.

[1384] The terms and expressions which have been employed in theforegoing specification are used therein as terms of description and notof limitation, and there is no intention, in the use of such terms andexpressions, of excluding equivalents of the features shown anddescribed or portions thereof, it being recognized that the scope of theinvention is defined and limited only by the claims which follow.

What is claimed is:
 1. A pharmaceutical composition comprising: (a) asolid dispersion comprising a low-solubility drug and a matrix, whereinat least a major portion of said drug in said dispersion is amorphous;and (b) a concentration-enhancing polymer, said dispersion being freefrom at least a portion of said concentration-enhancing polymer; whereinsaid composition provides improved stability of said drug relative to atleast one of a first control composition consisting of a mixture of saidlow-solubility drug in undispersed amorphous form and saidconcentration-enhancing polymer, and a second control compositionconsisting of a dispersion of said low-solubility drug and saidconcentration-enhancing polymer.
 2. A pharmaceutical compositioncomprising: (a) a solid dispersion comprising a low-solubility drug anda matrix, wherein at least a major portion of said drug in saiddispersion is amorphous; and (b) a concentration-enhancing polymer, saiddispersion being free from at least a portion of saidconcentration-enhancing polymer; wherein at least 10 wt % of said matrixis non-polymeric.
 3. A pharmaceutical composition comprising: (a) asolid dispersion comprising a low-solubility drug and a matrix, whereinat least a major portion of said drug in said dispersion is amorphous;and (b) a concentration-enhancing polymer, said dispersion being freefrom at least a portion of said concentration-enhancing polymer; whereinsaid concentration-enhancing polymer is non-cellulosic.
 4. Apharmaceutical composition, comprising: (a) a solid dispersioncomprising a low-solubility drug and a matrix, wherein at least a majorportion of said drug in said dispersion is amorphous; and (b) aconcentration-enhancing polymer, said dispersion being free from atleast a portion of said concentration-enhancing polymer, wherein saidconcentration-enhancing polymer is selected from the group consisting ofnon-ionizable cellulosic polymers and neutralized acidic polymers.
 5. Apharmaceutical composition, comprising: (a) a solid dispersioncomprising a low-solubility drug and a matrix, wherein at least a majorportion of said drug in said dispersion is amorphous; and (b) aconcentration-enhancing polymer, said dispersion being free from atleast a portion of said concentration-enhancing polymer, wherein saidconcentration-enhancing polymer is an ionizable cellulosic polymerhaving at least one of an ester-linked carboxylic acid-functionalaromatic substituent and an ether-linked carboxylic acid-functionalaromatic substituent.
 6. A pharmaceutical composition, comprising: (a) asolid dispersion comprising a low-solubility drug and a matrix, whereinat least a major portion of said drug in said dispersion is amorphous;(b) an amphiphilic, cellulosic concentration-enhancing polymer, saiddispersion being free from at least a portion of said amphiphilic,cellulosic concentration-enhancing polymer; (c) said amphiphiliccellulosic concentration-enhancing polymer having at least onehydrophobic substituent selected from the group consisting ofether-linked alkyl substituents, ester-linked alkyl substituents,ether-linked aryl substituents and ester-linked aryl substituents; (d)said amphiphilic cellulosic concentration-enhancing polymer having atleast one hydrophilic substituent selected from the group consisting ofether-linked hydroxy alkyl substituents, ester-linked hydroxy alkylsubstituents, alkyl ether groups, ester-linked ionizable substituents,and ether-linked ionizable substituents; and (e) provided that when saidconcentration-enhancing polymer has both the hydrophilic substituentshydroxypropyl and succinate, said polymer is free from both anether-linked methyl substituent and an ester-linked acetate substituent.7. The composition of claim 1 wherein said drug has improved physicalstability in said composition relative to said first controlcomposition.
 8. The composition of claim 7 wherein at least a majorportion of said drug is dissolved in said matrix.
 9. The composition ofclaim 7 wherein said drug has a solubility in said matrix that is atleast 30% of a concentration of said drug in said matrix.
 10. Thecomposition of claim 1 wherein said drug has a weight ratio to saidmatrix of said dispersion of less than
 20. 11. The composition of claim1 wherein said dispersion has a glass transition temperature that isgreater than a glass transition temperature of at least one of saidlow-solubility drug in undispersed amorphous form and said secondcontrol composition.
 12. The composition of claim 1 wherein saiddispersion has a glass transition temperature that is greater than about50° C. at 50% relative humidity.
 13. The composition of claim 1 whereinsaid drug in said dispersion has a crystallization rate that is lessthan 90% of a crystallization rate of said drug in undispersed amorphousform.
 14. The composition of claim 1 wherein said drug in saidcomposition has a relative degree of improvement in chemical stabilityof at least 1.25 relative to at least one of said first controlcomposition and said second control composition.
 15. The composition ofclaim 14 wherein said drug is acid-sensitive and saidconcentration-enhancing polymer is acidic.
 16. The composition of anyone of claims 2-6 wherein said drug in said composition has improvedstability relative to at least one of a first control compositionconsisting of a mixture of said low-solubility drug in undispersedamorphous form and said concentration-enhancing polymer, and a secondcontrol composition comprising a dispersion of said drug and saidconcentration-enhancing polymer.
 17. The composition of claim 16 whereinsaid drug has improved physical stability in said composition relativeto said first control composition.
 18. The composition of claim 17wherein at least a major portion of said drug is dissolved in saidmatrix.
 19. The composition of claim 17 wherein said drug has asolubility in said matrix that is at least 30% of a concentration ofsaid drug in said matrix.
 20. The composition of any one of claims 2-6wherein said drug has a weight ratio to said matrix of said dispersionof less than
 20. 21. The composition of any one of claims 2-6 whereinsaid dispersion has a glass transition temperature that is greater thana glass transition temperature of at least one of said low-solubilitydrug in undispersed amorphous form and said second control composition.22. The composition of any one of claims 2-6 wherein said dispersion hasa glass transition temperature that is greater than about 50° C. at 50%relative humidity.
 23. The composition of any one of claims 2-6 whereinsaid drug in said dispersion has a crystallization rate that is lessthan 90% of a crystallization rate of said drug in undispersed amorphousform.
 24. The composition of claim 16 wherein said drug in saidcomposition has a relative degree of improvement in chemical stabilityof at least 1.25 relative to at least one of said first controlcomposition and said second control composition.
 25. The composition ofclaim 24 wherein said drug is acid-sensitive and saidconcentration-enhancing polymer is acidic.
 26. The composition of claim2 wherein at least one component of said matrix is selected from thegroup consisting of alcohols, organic acids, organic bases, amino acids,sugars, fatty acid esters, alkyl sulfates, phospholipids, waxes andsalts.
 27. The composition of any one of claims 1, and 3-6 wherein atleast 10 wt % of said matrix is non-polymeric.
 28. The composition ofclaim 27 wherein at least one component of said matrix is selected fromthe group consisting of alcohols, organic acids, organic bases, aminoacids, sugars, fatty acid esters, alkyl sulfates, phospholipids, waxesand salts.
 29. The composition of any one of claims 1-6 wherein saidmatrix has at least one polymeric component.
 30. The composition ofclaim 29 wherein said at least one polymeric component of said matrix isselected from the group consisting of polyethylene glycols,polyoxyethylene glycols, polyethylene-polypropylene glycol copolymers,polyethylene oxides, polyvinylpyrrolidone, polyvinyl alcohols,polyethylene-vinyl alcohol copolymers, polyvinyl alcohol polyvinylacetate copolymers, carboxylic acid-functionalized polymethacrylates,amine-functionalized polymethacrylates, and proteins.
 31. Thecomposition of claim 29 wherein said at least one polymeric component ofsaid matrix is selected from the group consisting of xanthan gum,carrageenan, hydroxypropyl cellulose, hydroxypropyl methyl cellulose,carboxy methyl cellulose, chitosan, chitin, polydextrose, dextrin andstarch.
 32. The composition of any one of claims 1-6 wherein said drugis substantially amorphous in said dispersion.
 33. The composition ofany one of claims 1-6 wherein said dispersion is substantiallyhomogeneous.
 34. The composition of any one of claims 1-6 wherein saiddispersion is completely homogeneous.
 35. The composition of claim 32wherein said dispersion is substantially homogeneous.
 36. Thecomposition of any one of claims 1-6 wherein said composition is a solidmixture in which said concentration-enhancing polymer is suspended as aseparate phase within said dispersion.
 37. The composition of any one ofclaims 1-6 wherein said composition is a mixture of particles ofdispersion and particles of concentration-enhancing polymer.
 38. Thecomposition of claim 37 wherein said mixture is formed by at least oneof dry-granulation and wet-granulation.
 39. The composition of any oneof claims 1-6 wherein said dispersion and said concentration-enhancingpolymer are each in separate regions.
 40. The composition of any one ofclaims 1-6 further comprising a blend of concentration-enhancingpolymers selected from the group consisting of ionizable cellulosicpolymers, non-ionizable cellulosic polymers, ioniziable non-cellulosicpolymers, non-ionizable non-cellulosic polymers, and neutralized acidicpolymers.
 41. The composition of any one of claims 1-5 wherein saidconcentration-enhancing polymer has a hydrophobic portion and ahydrophilic portion.
 42. The composition of any one of claims 1-2wherein said concentration-enhancing polymer is a ionizable cellulosicpolymer.
 43. The composition of claim 42 wherein saidconcentration-enhancing polymer is selected from the group consisting ofhydroxypropyl methyl cellulose succinate, cellulose acetate succinate,methyl cellulose acetate succinate, ethyl cellulose acetate succinate,hydroxypropyl cellulose acetate succinate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl cellulose acetate phthalatesuccinate, cellulose propionate succinate, hydroxypropyl cellulosebutyrate succinate, hydroxypropyl methyl cellulose phthalate, celluloseacetate phthalate, methyl cellulose acetate phthalate, ethyl celluloseacetate phthalate, hydroxypropyl cellulose acetate phthalate,hydroxypropyl methyl cellulose acetate phthalate, cellulose propionatephthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetatetrimellitate, methyl cellulose acetate trimellitate, ethyl celluloseacetate trimellitate, hydroxypropyl cellulose acetate trimellitate,hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate succinate, cellulose propionatetrimellitate, cellulose butyrate trimellitate, cellulose acetateterephthalate, cellulose acetate isophthalate, cellulose acetatepyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropylsalicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate,hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acidcellulose acetate, ethyl nicotinic acid cellulose acetate, ethylpicolinic acid cellulose acetate, carboxy methyl cellulose, carboxyethyl cellulose, ethyl carboxy methyl cellulose, and blends thereof. 44.The composition of claim 42 wherein said concentration-enhancing polymeris selected from the group consisting of hydroxypropyl methyl celluloseacetate succinate, hydroxypropyl methyl cellulose phthalate, celluloseacetate phthalate, and cellulose acetate trimellitate, and blendsthereof.
 45. The composition of any one of claims 1-2 wherein saidconcentration-enhancing polymer is a non-ionizable cellulosic polymer.46. The composition of claim 45 wherein said concentration-enhancingpolymer is selected from the group consisting of hydroxypropyl methylcellulose acetate, hydroxypropyl methyl cellulose, hydroxypropylcellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethylcellulose acetate, and hydroxyethyl ethyl cellulose, and blends thereof.47. The composition of claim 4 wherein said concentration-enhancingpolymer is selected from the group consisting of hydroxypropyl methylcellulose acetate, hydroxypropyl methyl cellulose, hydroxypropylcellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethylcellulose acetate, and hydroxyethyl ethyl cellulose, and blends thereof.48. The composition of any one of claims 1-2 wherein saidconcentration-enhancing polymer is an ionizable, non-cellulosic polymer.49. The composition of claim 48 wherein said concentration-enhancingpolymer is selected from the group consisting of carboxylic acidfunctionalized polymethacrylates, carboxylic acid functionalizedpolyacrylates, amine-functionalized polyacrylates, amine-fuctionalizedpolymethacrylates, proteins, and carboxylic acid functionalizedstarches, and blends thereof.
 50. The composition of claim 3 whereinsaid concentration-enhancing polymer is selected from the groupconsisting of carboxylic acid functionalized polymethacrylates,carboxylic acid functionalized polyacrylates, amine-functionalizedpolyacrylates, amine-fuctionalized polymethacrylates, proteins, andcarboxylic acid functionalized starches, and blends thereof.
 51. Thecomposition of any one of claims 1-2 wherein saidconcentration-enhancing polymer is a non-ionizable, non-cellulosicpolymer.
 52. The composition of claim 51 wherein saidconcentration-enhancing polymer is selected from the group consisting ofvinyl polymers and copolymers having at least one substituent selectedfrom the group consisting of hydroxyl, alkylacyloxy, and cyclicamido;vinyl copolymers of at least one hydrophilic, hydroxyl-containing repeatunit and at least one hydrophobic, alkyl- or aryl-containing repeatunit; polyvinyl alcohols that have at least a portion of their repeatunits in the unhydrolyzed form, polyvinyl alcohol polyvinyl acetatecopolymers, polyethylene glycol polypropylene glycol copolymers,polyvinyl pyrrolidone, and polyethylene polyvinyl alcohol copolymers,and blends thereof.
 53. The composition of claim 3 wherein saidconcentration-enhancing polymer is selected from the group consisting ofconsisting of vinyl polymers and copolymers having at least onesubstituent selected from the group consisting of hydroxyl,alkylacyloxy, and cyclicamido; vinyl copolymers of at least onehydrophilic, hydroxyl-containing repeat unit and at least onehydrophobic, alkyl- or aryl-containing repeat unit; polyvinyl alcoholsthat have at least a portion of their repeat units in the unhydrolyzedform, polyvinyl alcohol polyvinyl acetate copolymers, polyethyleneglycol polypropylene glycol copolymers, polyvinyl pyrrolidone, andpolyethylene polyvinyl alcohol copolymers, and blends thereof.
 54. Thecomposition of claim 5 wherein said concentration-enhancing polymer isselected from the group consisting of hydroxypropyl cellulose acetatephthalate succinate, hydroxypropyl methyl cellulose phthalate, celluloseacetate phthalate, methyl cellulose acetate phthalate, ethyl celluloseacetate phthalate, hydroxypropyl cellulose acetate phthalate,hydroxypropyl methyl cellulose acetate phthalate, cellulose propionatephthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetatetrimellitate, methyl cellulose acetate trimellitate, ethyl celluloseacetate trimellitate, hydroxypropyl cellulose acetate trimellitate,hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate succinate, cellulose propionatetrimellitate, cellulose butyrate trimellitate, cellulose acetateterephthalate, cellulose acetate isophthalate, cellulose acetatepyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropylsalicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate,hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acidcellulose acetate, ethyl nicotinic acid cellulose acetate, ethylpicolinic acid cellulose acetate, carboxy methyl cellulose, carboxyethyl cellulose, ethyl carboxy methyl cellulose, and blends thereof. 55.The composition of claim 6 wherein said amphiphilic, cellulosicconcentration-enhancing polymer is selected from the group consisting ofhydroxypropyl cellulose acetate succinate, hydroxypropyl methylcellulose, hydroxypropyl methyl cellulose acetate, hydroxypropyl methylcellulose succinate, hydroxypropyl methyl cellulose phthalate,hydroxypropyl methyl cellulose acetate phthalate, hydroxyethyl methylcellulose, hydroxyethyl methyl cellulose succinate, hydroxyethylcellulose acetate succinate, hydroxyethyl methyl cellulose acetatesuccinate, hydroxyethyl methyl cellulose acetate phthalate, hydroxyethylcellulose acetate, hydroxyethyl ethyl cellulose, carboxymethyl ethylcellulose, cellulose acetate phthalate, hydroxypropyl cellulose acetatephthalate, methyl cellulose acetate phthalate, ethyl cellulose acetatephthalate, hydroxypropyl cellulose acetate phthalate succinate,cellulose propionate phthalate, hydroxypropyl cellulose butyratephthalate, cellulose acetate trimellitate, methyl cellulose acetatetrimellitate, ethyl cellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate, hydroxypropyl methyl cellulose acetatetrimellitate, hydroxypropyl cellulose acetate trimellitate succinate,cellulose propionate trimellitate, cellulose butyrate trimellitate,cellulose acetate terephthalate, cellulose acetate isophthalate,cellulose acetate pyridinedicarboxylate, salicylic acid celluloseacetate, hydroxypropyl salicylic acid cellulose acetate, ethylbenzoicacid cellulose acetate, hydroxypropyl ethylbenzoic acid celluloseacetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic acidcellulose acetate, and ethyl picolinic acid cellulose acetate, andblends thereof.
 56. A composition of any one of claims 1, 2 and 3wherein said concentration-enhancing polymer is a neutralized acidicpolymer.
 57. The composition of any one of claims 5 and 6 wherein atleast a portion of said concentration-enhancing polymer is neutralized.58. The composition of any one of claims 1-6 wherein said compositionwhen administered to a use environment provides a dissolution area underthe concentration versus time curve for a time period of at least 90minutes during the 270 minutes immediately following introduction tosaid use environment that is at least 1.25-fold the corresponding areaunder the curve provided by a control composition comprising anequivalent amount of undispersed amorphous drug alone.
 59. Thecomposition of any one of claims 1-6 wherein said composition whenadministered to a use environment provides a maximum concentration ofsaid drug in said use environment that is at least 1.25-fold a maximumconcentration of said drug provided by a control composition comprisingan equivalent amount of undispersed amorphous drug alone.
 60. Thecomposition of any one of claims 1-6 wherein said composition whenadministered to an animal provides a relative bioavailability of atleast 1.25 relative to a control composition comprising an equivalentamount of undispersed amorphous drug alone.
 61. The composition of anyone of claims 1-6 wherein said composition when administered to a useenvironment provides a dissolution area under the concentration versustime curve for a time period of at least 90 minutes during the 270minutes immediately following introduction to said use environment thatis at least 1.25-fold the corresponding area under the curve provided bya control composition comprising an equivalent amount of said dispersionbut with no concentration-enhancing polymer.
 62. The composition of anyone of claims 1-6 wherein said composition when administered to a useenvironment provides a maximum concentration of said drug in said useenvironment that is at least 1.25-fold a maximum concentration of saiddrug provided by a control composition comprising an equivalent amountof said dispersion but with no concentration-enhancing polymer.
 63. Thecomposition of any one of claims 1-6 wherein said composition whenadministered to an animal provides a relative bioavailability of atleast 1.25 relative to a control composition comprising an equivalentamount of said dispersion but with no concentration-enhancing polymer.64. The composition of any one of claims 1-6 wherein said drug isselected from the group consisting of antihypertensives, antianxietyagents, anticlotting agents, anticonvulsants, blood glucose-loweringagents, decongestants, antihistamines, antitussives, antineoplastics,beta blockers, anti-inflammatories, antipsychotic agents, cognitiveenhancers, cholesterol-reducing agents, antiobesity agents, autoimmunedisorder agents, anti-impotence agents, antibacterial and antifungalagents, hypnotic agents, anti-Parkinsonism agents, anti-Alzheimer'sdisease agents, antibiotics, anti-depressants, antiviral agents,anti-atherosclerotic agents, glycogen phosphorylase inhibitors, andcholesterol esterase transfer protein inhibitors.
 65. The composition ofany of claims 1-6, wherein the drug comprises a glycogen phosphorylaseinhibitor, a CETP inhibitor or a CCR1 inhibitor.
 66. The composition ofany of claim 1-6, wherein the drug comprises[R-(R′S′)]-5-chloro-N-[2-hydroxy-3-{methoxymethylamino}-3-oxo-1-(phenylmethyl)propyl-1H-indole-2-carboxamideor 5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide.67. The composition of any of claims 1-6, wherein the drug comprises[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester; [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester; or [2R, 4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1carboxylicacid isopropyl ester.
 68. The composition of claims 1-6, wherein thedrug comprises quinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-3-fluorobenzyl-2(S),7-dihydroxy-7-methyl-octyl]amide;quinoxaline-2-carboxylic acid[1-benzyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide;or quinoxaline-2-carboxylic acid[1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide.69. A method of administering a drug comprising co-administering to apatient in need of said drug: (a) a solid dispersion comprising alow-solubility drug and a matrix, wherein at least a major portion ofsaid drug in said dispersion is amorphous; and (b) aconcentration-enhancing polymer, said dispersion being free from atleast a portion of said concentration-enhancing polymer; wherein saiddispersion provides improved stability of said drug relative to at leastone of a first control composition consisting of a mixture of saidlow-solubility drug in undispersed amorphous form and saidconcentration-enhancing polymer, and a second control compositionconsisting of a dispersion of said low-solubility drug and saidconcentration-enhancing polymer.
 70. The method of claim 69 wherein saiddispersion is administered separately from said concentration-enhancingpolymer.
 71. The method of claim 70 wherein said dispersion and saidconcentration-enhancing polymer are administered at approximately thesame time.
 72. The method of claim 71 wherein said dispersion and saidconcentration-enhancing polymer are present in a single dosage form. 73.A method of administering a drug comprising co-administering to apatient in need of said drug: (a) a solid dispersion comprising alow-solubility drug and a matrix, wherein at least a major portion ofsaid drug in said dispersion is amorphous; and (b) aconcentration-enhancing polymer, said dispersion being free from atleast a portion of said concentration-enhancing polymer; wherein atleast 10 wt % of said matrix is non-polymeric.
 74. A method ofadministering a drug comprising co-administering to a patient in need ofsaid drug: (a) a solid dispersion comprising a low-solubility drug and amatrix, wherein at least a major portion of said drug in said dispersionis amorphous; and (b) a concentration-enhancing polymer, said dispersionbeing free from at least a portion of said concentration-enhancingpolymer; wherein said concentration-enhancing polymer is non-cellulosic.75. A method of administering a drug comprising co-administering to apatient in need of said drug: (a) a solid dispersion comprising alow-solubility drug and a matrix, wherein at least a major portion ofsaid drug in said dispersion is amorphous; and (b) aconcentration-enhancing polymer, said dispersion being free from atleast a portion of said concentration-enhancing polymer, wherein saidconcentration-enhancing polymer is selected from the group consisting ofnon-ionizable cellulosic polymers and neutralized acidic polymers.
 76. Amethod of administering a drug comprising co-administering to a patientin need of said drug: (a) a solid dispersion comprising a low-solubilitydrug and a matrix, wherein at least a major portion of said drug in saiddispersion is amorphous; and (b) a concentration-enhancing polymer, saiddispersion being free from at least a portion of saidconcentration-enhancing polymer, wherein said concentration-enhancingpolymer is an ionizable cellulosic polymer having at least one of anester-linked carboxylic acid-functional aromatic substituent and anether-linked carboxylic acid-functional aromatic substituent.
 77. Amethod of administering a drug comprising co-administering to a patientin need of said drug: (a) a solid dispersion comprising a low-solubilitydrug and a matrix, wherein at least a major portion of said drug in saiddispersion is amorphous; (b) an amphiphilic, cellulosicconcentration-enhancing polymer, said dispersion being free from atleast a portion of said amphiphilic, cellulosic concentration-enhancingpolymer; (c) said amphiphilic cellulosic concentration-enhancing polymerhaving at least one hydrophobic substituent selected from the groupconsisting of ether-linked alkyl substituents, ester-linked alkylsubstituents, ether-linked aryl substituents and ester-linked arylsubstituents; (d) said amphiphilic cellulosic concentration-enhancingpolymer having at least one hydrophilic substituent selected from thegroup consisting of ether-linked hydroxy alkyl substituents,ester-linked hydroxy alkyl substituents, alkyl ether substituents,ester-linked ionizable substituents, and ether-linked ionizablesubstituents; and (e) provided that when said concentration-enhancingpolymer has both the hydrophilic substituents hydroxypropyl andsuccinate, said polymer is free from both an ether-linked methyl groupand an ester-linked acetate group.